Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta-analysis.

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 08/03/14 For personal use only.

Review

1.

Introduction

2.

Methods of improving solubility and dissolution

3.

Complexation

4.

CD complexes

5.

PL complexation

6.

Expert opinion

Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta-analysis Ajay Semalty H.N.B. Garhwal University Srinagar (Garhwal), Department of Pharmaceutical Sciences, Chauras Campus, Srinagar, India

Introduction: Poor solubility and dissolution of drugs are the major challenges in drug formulation and delivery. In order to improve the solubility and dissolution profile of drugs, various methods have been investigated so far. The cyclodextrin (CD) complexation and phospholipid (PL) complexation are among the exhaustively investigated methods employed for more precise improvement of the solubility and dissolution of poorly water-soluble drugs. Areas covered: The article discusses the CD and PL complexation techniques of solubility and dissolution enhancement. Various studies reporting the CD and PL complexation as the potential approaches to improve the dissolution, absorption and the bioavailability of the drugs have been discussed. The article critically reviews the physicochemical properties of CDs and PLs, eligibility of drugs for both the complexation, thermodynamics of complexation, methods of preparation, characterization, advantages, limitation and the meta-analysis of some studies for both the techniques. Expert opinion: The CD and PL complexation techniques are very useful in improving solubility and dissolution (and hence the bioavailability) of biopharmaceutical classification system Class II and Class IV drugs. The selection of a particular kind of complexation can be made on the basis of eligibility criteria (of drugs) for the individual techniques, cost, stability and effectiveness of the complexes. Keywords: complexation, differential scanning calorimetry, dissolution, phospholipids, solubility, X-ray powder diffraction Expert Opin. Drug Deliv. (2014) 11(8):1255-1272

1.

Introduction

Poor solubility and dissolution of drugs are the two major challenges that formulation scientists face most of the time. The drugs that have water solubility < 10 mg/ml (over the pH range of 1 -- 7 at 37 C) show the potential bioavailability (BA) problems. The BA of the drugs that show the dissolution rate limited absorption may be improved by improving their aqueous solubility. Moreover, the various formulations need water solubility of the drug as a prerequisite. Various techniques like solid dispersion, solvent deposition, supercritical fluid process, micronization, use of surfactants, use of salt forms, and complexation have been investigated for resolving the solubility issue in pharmaceutical product development [1-8]. Each of these techniques has its own merits and some demerits. Out of these, the complexation technique has been employed more precisely to improve the solubility and the dissolution of poorly water-soluble drugs. Among the complexation techniques phospholipid (PL) complexation and cyclodextrin (CD) complexation are the two most widely investigated approaches for improving solubility. Developing the drugs as lipid or CD complexes has been 10.1517/17425247.2014.916271 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

1255

A. Semalty

. .


.

.

.

.

Coordination complexes Coordination complexes are formed by coordinate bonds in which a pair of electrons is, in some degree, transferred from one interactant to the other. The most important examples are the metal--ion coordination complexes between metal ions and bases. 3.1

Article highlights. Poor solubility and the dissolution of drugs are the major challenges in drug formulation and drug delivery. Cyclodextrin (CD) complexation and phospholipid (PL) complexation are among the exhaustively investigated methods of solubility and dissolution improvement for biopharmaceutical classification system (BCS) Class II and IV drugs. The eligibility criterion for the CD complex is rather more geometric than the chemical as compared to the PL complexation. Apart from the improvement in solubility, the PL complexes may also improve the lipid solubility or the permeability of BCS Class IV drugs leading to improved bioavailability of permeability rate limiting drugs also. Both kinds of complexation lead to the amorphization of drug in the complex with more pronounced amorphization in PL complexes. Both the complexes show distinguished characteristic results for differential scanning calorimetry, X-ray diffractometry, solubility and dissolution study.

This box summarizes key points contained in the article.

proven to be a potential approach for improving solubility and minimizing the GI toxicity of drugs. The article focuses on the critical review and meta-analysis of these two techniques for improving aqueous solubility and dissolution.

Methods of improving solubility and dissolution

Molecular complexes Molecular complexes are formed by noncovalent interactions between the substrate and ligand. Among the kinds of complex species included in this class are small molecule--small molecule complexes, small molecule--macromolecule species, ion-pairs, dimers and other self-associated species, and inclusion complexes in which one of the molecules, the ‘host’, forms or possesses a cavity into which it can admit a ‘guest’ molecule. Although the classification of complexes is somewhat arbitrary, the differentiation is usually based on the types of interactions and species involved, for example, metal complexes, molecular complexes, inclusion complexes and ionexchange compounds. Most pharmaceutically useful systems are inclusion complexes and molecular complexes between small molecules. Among the complexation techniques the PL complexation and CD complexation are the two most widely investigated approaches for improving the solubility. As the present article is focused on these two techniques for their potential in improving aqueous solubility and dissolution, they shall be reviewed in the following sections. 3.2

2.

Solubility and dissolution can be improved by the pharmaceutical approach that involves modification of formulation manufacturing process or the physicochemical properties of drugs without changing the chemical structure. The modulation of biopharmaceutical properties is a key approach to improve the BA of drugs. Solubility and dissolution being the biopharmaceutical properties can play their vital role in improving BA of these drugs. Various methods and techniques used for improving solubility and dissolution of poorly water-soluble drugs have been reported (Table 1). 3.

Complexation

Each of the techniques used for improving solubility and dissolution has its own merits and some demerits. Out of these, the complexation technique has been employed more precisely to improve the solubility and dissolution of poorly water-soluble drugs. Complexation is generally defined as the reversible association of a substrate and ligand to form a new species. On the basis of the type of chemical bonding, complexes can generally be classified into two groups [9]. 1256

4.

CD complexes

Structures and physicochemical properties of CDs CDs (Figure 1) are the cyclic carbohydrates formed during the bacterial (Bacillus macerans) degradation of starch by CD glucosyltransferase bacterial enzymes and used as the potential complexing agents to form inclusion complex with poorly water-soluble drugs. These are amphiphilic molecules (cyclic oligosaccharides) and consist of (a-1,4) linked a-D-glucopyranose units with a lipophilic central cavity and a hydrophilic outer surface. As a consequence of the 4C1 conformation of the -a-dglucose residues and lack of free rotation about glycosidic bonds, the compounds are not perfectly cylindrical molecules, but are somewhat cone shaped. So CDs are shaped like a truncated cone because of chair conformation of glucopyranose units, with hydroxyl group oriented towards the exterior (primary hydroxyl group towards the narrow edge of cone and secondary hydroxyl groups towards the wider edge). Due to this conformation CD contain the lipophilic central cavity that is lined by the skeletal carbons and ethereal oxygen of glucose residues and hydrophilic outer surface [10]. The microenvironment in their central cavity is relatively non-polar and lipophilic. Three types of CD -- a, b, g -- consist of six, seven and eight glucopyranose units, 4.1

Expert Opin. Drug Deliv. (2014) 11(8)

Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement

Table 1. Methods of improving solubility, dissolution and bioavailability [1-8,91-93].


Methods

Mechanism involved

Methodology

Use of co-solvent

Increase in solubility of drug

Micellization/use of surfactants Hydrotrophy/mixed hydrotrophy method

By promoting wetting and penetration of dissolution fluid into the drug Addition of large amounts of a second solute (or the combination of two) results in an increase in the aqueous solubility of another solute Improving solubility by preparing sol-gel form of the drug Decreasing the drug’s particle size changes the microenvironment of the drug particle, which increases the dissolution rate and absorption When exposed to water the soluble carrier dissolves leaving the drug in micro crystalline state which solubilizes rapidly Increasing the effective surface area of drug by decreasing particle size

Use of solid solution Solid dispersion

Eutectic mixture

Micronization

By addition of polar group

Increasing water solubility by increasing hydrogen bonding and interaction with water

Alternation of pH of solvent Use of metastable polymorphs

Changing the pH of drug in solution

Solvates formation

Powder of submicron size having increased surface area and show improved solubility Weak physical interaction between adsorbate and adsorbant through hydration and swelling of clay in aqueous media improves solubility Inclusion of hydrophobic groups of drug in the core of CD cavity and thereby improving solubility Drug-Lipid complexes improve amorphous nature of drug in the complexes and being amphiphilic in nature the complex show improved solubility and dissolution

Selective absorption on insoluble carrier

CD complexation

Phospholipid complexation

Metastable forms show better solubility than stable forms

Examples

Addition of co-solvent ethanol, propylene, glycol, glycerin Addition of suitable surfactants (polysorbate) Addition of hydrotropic agents (s) like urea, nicotinamide etc.

Analgesic syrups of paracetamol Spironolactone

Fusion, melting

Succinic acid

Prepared by fusion, solvent evaporation fusion solvent method

Paracetamol-urea

Fusion

Paracetamol-camphor

By spray drying and by use of fluid energy mill

Griesiofulvin and several steroidal and sulfa drugs --

Addition of polar group in the structure of drug (carboxylic acid and amine) Salt formation, addition of buffer Converting the stable form to metastable form Freeze drying of solute with organic solvent Use of highly active adsorbent, clay-like bentonite

Paracetamol

Buffered tablets of aspirin Using B form of chloramphenicol than A and C forms Benzene solvate Indomethacin, prednisone

Formation of drug complex with CD (a, b, g)

Meloxicam, phenytoin

The phospholipid complexes of drug without the presence of covalent bond are formed

Aceclofenac, aspirin, curcumin, silybin etc.

CD: Cyclodextrin.

Figure 1. Conformation and numbering of the cyclodextrins.

respectively, and are the most widely investigated CDs. CDs containing 9, 10, 11, 12 and 13 glucopyranose units, which are designated as d, ", z, h and q-CD, respectively, have also been reported.

Natural CD substitution of any of the hydrogen bond forming hydroxyl groups improves their aqueous solubility. CD derivatives of pharmaceutical interest include the hydroxypropyl derivatives of b- and g-CD, the randomly methylated b-CD, sulfobutylether b-CD and the branched CDs such as glucosyl-b-CD. It has been found that for the solubility or dissolution rate limiting drugs, CDs complexation may be a potential approach to improve the dissolution, absorption and the BA [11-16]. Most of the CD derivatives presently in application are synthesized from b-CD. Suitable chemical modification leads to amorphous or at least partially crystalline CD derivatives with high aqueous solubility and considerably reduced parenteral toxicity, depending on the type, degree and patterns of


1257

A. Semalty

complexes prevent dissolution rate limited absorption of the drug. . CDs complexation can only be used with drugs that possess high (dose 0.1 mg/kg) to average (dose 1 mg/kg) potency. This can be explained by the fact that the upper limit in size of conventional oral tables is about 800 mg. Therefore, to account for the excipient requirement only 700 mg of the complex (or 70 -- 150 mg of drug) can be added in conventional immediate release tablets [12].

Table 2. Properties of some cyclodextrins.


CDs

Molecular weight (Da)

a-CD 972 b-CD 1135 2-Hydroxypropyl-b-CD 1400 Randomly methylated b-CD 1312 b-CD sulfobutyl ether sodium salt 2163 g-CD 1297 2-Hydroxypropyl-g-CD 1576

Water solubility at 25 C (mg/ml) 14.5 18.5 > 600 > 500 > 500 232 > 500

Other general requirements for the drug candidate for inclusion complexation are as follows.

CD: Cyclodextrin.

. Its melting point should be below 250 and 270 C

substitution. The two modified CDs that have received the greatest attention are the hydroxypropyl-b-CDs and sulfobutylether-b-CDs (SBE-b-CDs; mainly as [SBE]7M-b-CD). The solubility of underivatized CDs generally increases with increasing temperature. On the other hand, the aqueous solubility of methylated CDs is inversely proportional to temperature (Table 2). They exhibit enhanced thermal stability with a decomposition temperature approaching 300 C. But an increase in temperature may cause the dehydration of methylated CDs in a manner similar to nonionic surfactants. CDs are fairly stable in alkaline media, whereas they are hydrolytically cleaved by strong acids to give linear oligosaccharides [17]. Their ring structure has neither a reducing nor a non-reducing end-group. They are rather resistant to many common a amylases, and completely resistant to yeast fermentation and b amylases. Selection of drugs for CD complexation For improving the solubility and dissolution of the drugs formulated as the immediate release oral dosage forms, the CD complexation approach can be explored on the basis of the following two basic requirements. 4.2

. The aqueous solubility of the drug/CD complex in the

gastrointestinal tract has to be sufficient to prevent dissolution rate-limited absorption of the drug. Therefore, the CD complexation is a suitable approach for the drugs, which shows that the aqueous solubility is < 0.1 -- 0.05 mg/ml. The biopharmaceutical classification system (BCS) classifies the drug in four classes on the basis of solubility and permeability (Table 3) [1]. BCS states that for a Class I drug, the maximum doseto-solubility (D:S) ratio has to be below about 250 ml in the pH range of 1 -- 7.5 for immediate-release oral dosage forms [12,15]. Drugs with aqueous solubility greater than 0.1 -- 0.05 mg/ml generally do not exhibit dissolution rate-limiting absorption after oral administration in a conventional immediate-release tablet. Therefore, the drugs of classes II and IV are the most eligible for CD complexation provided that their 1258

(otherwise cohesive forces between molecules are too strong). . The molecule should consist of < 5 condensed rings (otherwise it may be too big). . It should have polarity less than that of water. The polarity inside the cavity has been measured to be that of an aqueous alcoholic solution. . Its molecular weight should be between 100 and 400 (with smaller molecules the drug content of complex is too low. On the other hand, larger molecules do not fit into a single CD cavity in 1:1 complex, so CDs may be required in higher ratios of 1:2, 1:3 and so on for these). The formation of inclusion complexes of drugs with CDs largely depends on the compound’s size compatibility with the dimensions of the CD cavities. The stability of a complex also depends, however, on other properties of the guest molecule, such as its polarity. Compounds used medicinally usually are large molecules. Therefore, it is very commonly observed that the complexes form such that only certain groups or side chains penetrate into the carbohydrate channel. It has been reported that geometrical, rather than chemical, factors are decisive in determining the kinds of guest molecules that can penetrate into the CD cavity to form an inclusion complex [17]. A 1:2 (guest:CD) complex may be formed when the guest molecule is too large to find complete accommodation in one cavity and its other end is also amenable to complex formation. Some examples are the complexes of b-CD with prostaglandins, vitamin D and indomethacin [10-12,17]. The stability of the complex is proportional to the hydrophobic character of the substituents; thus, a methyl or ethyl substituent will increase the stability. Hydroxyl groups (of aromatic rings) hinder complex formation, and their hydrophilic effects decrease in the order ortho > meta > para. In the case of amine groups, it is important whether they are present in their neutral or ionized form. Ionic species usually do not form stable complexes [18]. Thermodynamics of CD complexation An inclusion complex is formed when a macrocyclic compound possessing an intramolecular cavity of molecular 4.3




Table 3. Biopharmaceutical classification system of drugs Class

Solubility

Permeability

I

High

High

II

Low

High

III

High

Low

IV

Low

Low

General properties of drugs of the class

Examples of the class

Water soluble (high CS value resulting in a high CAq value); well absorbed from GIT (larger P values); lipophilic with a MW £ 500 Da and aqueous solubility ‡ 1 mg/ml; D:S £ 250 ml Relatively lipophilic and water-insoluble drugs (CS £ 0.1 mg/ml); well absorbed from GIT (large P values); D:S ‡ 250 ml

Paracetamol, piroxicam*, propranolol, theophylline, rofecoxcib

Water soluble (high CS and high CAq); do not readily permeate biomembranes (low P); D:S £ 250 ml Water insoluble (Low CS and low CAq); do not readily permeate biomembranes (low P); D:S ‡ 250 ml

Carbamazepine, digoxin, cinnarizine, glibeclamide, miconazole, nimesulide, nifedipine, phenytoin, spironolactone, tolbutamide, itraconazole Acyclovir, atenolol, ranitidine, diphenhydramine Furosemide, cyclosporine A

*Piroxicam is practically insoluble in water but is a potent drug with low enough D:S ratio to be classified as a Class I drug. CAq: Drug concentration in the aqueous exterior immediately adjacent to the mucosal surface; CS: Saturation solubility of the drug in the aqueous fluid; D:S: Dose-to-solubility ratio; P: Permeability coefficient of the drug through the lipophilic mucosa.

Hydrophilic Exterior HO CH OH CH

Hydrophobic cavity

Hydrophobic drug

Drug: CD complex

CH2OH

Figure 2. Complexation of drugs inside the hydrophobic cavity of CDs. CD: Cyclodextrin.

dimension interacts with a small molecule that can enter the cavity. The macrocylic molecule is called the ‘host’ and the small included molecule is called the ‘guest’. The CD complexes are formed when a guest molecule is partially or fully included inside a host molecule, for example, CD with no covalent bonding (Figure 2). When inclusion complexes are formed, the physicochemical parameters of the guest molecule are disguised or altered and improvements in the molecule’s solubility, stability, taste, safety, BA and so on are commonly seen. The standard free-energy decrease associated with formation of CD inclusion complexes is generally owing to a negative standard enthalpy change (DH ) accompanying the inclusion process. The standard entropy change (DS ) can be either positive or negative, although the majority of guest molecules that have been studied appear to have negative (DS ) values. Several intermolecular interactions have been proposed as being responsible for the formation of CD inclusion complexes in an aqueous solution [19]. They are: i) hydrophobic

interaction; ii) van der Waals interaction, mainly induction and dispersion forces; iii) hydrogen-bonding and dipole-dipole interactions; iv) the release of ‘high-energy water’ from the CD cavity on substrate inclusion; and v) the release of conformational strain in a CD-water adduct, together with the formation of a hydrogen-bonding network around the O(2), O(3) side of the CD macrocycle on substrate inclusion. As the values of DH and DS for complex formation vary over such a wide range, it is reasonable to conclude that the various intermolecular interactions described here act simultaneously, and the extent to which these interactions contribute may largely depend on the nature of host and guest molecules. Methods of preparation of CD complexes The methods used to prepare the CD complexes are as follows [20-26]. The complexation effectiveness is dependent on the properties of the complexes formed and the preparation methods. The ability to make consistently the complexes 4.4


1259

A. Semalty

with reproducible properties should be evaluated when developing methods for complex preparation. Solvent evaporation method In this method drug and the CD are dissolved in a common solvent and the resultant molecular dispersion of drug and complexing agent is evaporated off under vacuum [20]. The complete evaporation of the solvent yields the solid powdered inclusion complex. In general the drug and CD are taken in 1:1 or 1:2 molar ratios depending on the geometrical fitness of the drug molecule.

uncomplexed free drug and CDs an adequate amount of solvent mixture is added to the reaction mixture. The complex is obtained as the precipitate, which is filtered and dried [23].


4.4.1

Physical blending method The drug and CD are mixed together thoroughly with mechanical trituration (in mortar for the laboratory scale). The resultant mass is passed through a suitable sieve (according to the desired particle size). In industries the physical mixture is prepared with extensive blending of the drug with CDs in a rapid mass granulator [21]. 4.4.2

Kneading method The CDs are impregnated with a little amount of water or hydroalcoholic solution to convert into the paste. The drug is then added to the paste and kneaded for a specific time. The kneaded mixture is then dried and passed through a sieve as per the requirement. In laboratory scale kneading can be achieved by using mortar and pestle. In large scale the kneading can be done by utilizing extruders and other machines [8,27]. 4.4.3

Co-precipitation technique In a solution of CD, drug is added and agitated (on magnetic stirrer) in a controlled manner. The formed precipitate is separated by vacuum filtration and dried at room temperature. This technique leaves a drug--CD solution in very close condition to the saturation and through abrupt change of temperature with addition of organic solvent. But this method is not used much on an industrial scale due to low yield, risk of using organic solvents and longer time required for the preparation [8,28]. 4.4.4

Neutralization precipitation method In this method the drug is dissolved in alkaline solution like sodium/ammonium hydroxide, then mixed with aqueous solution of CDs resulting in a clear solution. This clear solution is neutralized under agitation using hydrochloric acid solution till reaching the equivalent point. This leads to the precipitation of the complex, which is filtered and dried [22,23]. 4.4.5

Microwave irradiation method Drug and CDs are taken in definite molar ratio, dissolved in a mixture of water and organic solvent (in a specific proportion), kept in a microwave oven for about 1 -- 2 min at 60 C, and after this reaction to remove the residual, 4.4.6

1260

Milling/co-grinding method A solid binary inclusion compounds can be prepared by grinding and milling of the drug and CDs with the help of mechanical devices [24]. Drug and CDs are mixed intimately and the physical mixture is introduced in an oscillatory mill and ground for suitable time. Alternatively, the ball milling process can also be utilized for preparation of the drug--CD binary system. The ball mill containing balls of varied sizes is operated at a specified speed for a predetermined time, and then it is unloaded, sieved through a 60-mesh sieve. This technique is superior to other approaches from an economic as well as environmental standpoint in that unlike similar methods it does not require any toxic organic solvents. This method differs from the physical mixture method where simple blending is sufficient and in co-grinding, extensive combined attrition and impact effect on powder blend is required. 4.4.7

Atomization/spray-drying method Spray-drying is a common and widely used technique of producing a dry powder from a liquid phase in the pharmaceutical industry. It is also used as a preservation method, increasing the storage stability due to the water elimination. In this technique the mixture is atomized and then the produced spray is dried with the tangentially entering hot air leading to the spray-dried CD complex. The technique shows a high efficiency in forming complex. Besides, the product obtained by this method yields porous particles in a more uniform size and shape, which in turn improves the dissolution rate of drug in complex form [21]. 4.4.8

Lyophilization/freeze-drying method In order to get a porous, amorphous powder with a high degree of interaction between drug and CD, lyophilization/freezedrying technique is considered as a suitable technique [3,8]. In this technique, the solvent system from the solution is eliminated through a primary freezing (at about -30 to - 40 C) and subsequent drying of the solution containing both drug and CD at reduced pressure (about 30 -- 40 N/m2). After the material is frozen the vapor sublimes from the surface and this leads to the receding of the ice front into the solid in a similar manner to drying (during the second falling rate period of the ordinary process). The traces of moisture are removed by secondary drying, which involves the exposure to a high temperature (50 to - 60 C) for a short period of time. Thermolabile substances can be successfully made into complex form by this method. The limitations of this technique are that it is a time-consuming process and the yield is a poor-flowing powdered product. Lyophilization/freeze-drying technique is considered as an alternative to solvent evaporation and involves molecular mixing of drug and carrier in a common solvent. 4.4.9




4.4.10

Supercritical antisolvent technique

Since its inception in late 1980s a number of techniques have been developed and patented in the field of supercritical fluidassisted particle design [2]. In the supercritical fluid antisolvent technique, carbon dioxide is used as antisolvent for the solute but as a solvent with respect to the organic solvent. The use of supercritical carbon dioxide is advantageous as its low critical temperature and pressure make it attractive for processing heat-labile pharmaceuticals. Also, it is non-toxic, nonflammable, inexpensive and is much easier to remove from the polymeric materials when the process is complete; even though a small amount of carbon dioxide remains trapped inside the polymer, it poses no danger to the consumer. Supercritical particle generation processes are a new and efficient route for improving BA of pharmaceutically active compounds. In this technique, drug and CD are dissolved in a proper solvent then the solution is fed into a pressure vessel under supercritical conditions, through a nozzle (i.e., sprayed into supercritical fluid antisolvent). When the solution is sprayed into supercritical fluid antisolvent, the antisolvent rapidly diffuses into that liquid solvent as the carrier liquid solvent counter diffuses into the antisolvent. Because the supercritical fluid expanded solvent has lower solvent power than the pure solvent, the mixture becomes supersaturated resulting in the precipitation of the solute and the solvent is carried away with the supercritical fluid flow [25,26].

possible to get the single crystal X-ray pattern to elucidate the structure of the complex. In the XRPD the peak position (angle of diffraction) is an indication of crystal structure and peak heights are the measures of sample crystallinity (crystallite size) in a diffractogram. In a recent study, X-ray diffraction pattern of Racecadotril-b-CD complex exhibited disappearance and reduction in the intensity of large diffraction peaks in which it was no longer possible to distinguish the characteristic peak of the drug indicating the decrease in crystallinity or partial amorphization of the drug. The result confirmed that Racecadotril was no longer present as a crystalline material in its b-CD complex and existed in the amorphous state [27]. Fourier transform infrared spectroscopy Complex formation may be supported by IR spectroscopy either in the solid or in the solution state in some cases, although the application of IR is limited to guests having characteristic absorption bands, such as carbonyl or sulfonyl groups. In most cases, however, no change due to complex formation can be observed. Bands due to the included part of the guest molecule do shift or their intensities are altered, but since the mass of the guest molecule does not exceed 5 -- 15% of the mass of the complex, these alterations are usually obscured by the spectrum of the host. Therefore, no useful information can be obtained [17]. 4.5.3

X-ray crystallography X-ray crystallography should be the ultimate tool for understanding crystalline complex structures. Many crystalline structures of complexes formed by natural CDs have been reported [19]. This technique is less useful for studying complexes formed with CD derivative since almost all the complexes formed with water-soluble CD derivatives are amorphous.

4.5

Characterization of CD complexes Several methods have been used to characterize complexes in solid state. Apart from the most basic method of evaluation, that is, phase solubility study, the most commonly used other methods are differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and X-ray crystallography. In recent years, the NMR method has also showed many utilities [29-31].

4.5.4

4.5.1

Differential scanning calorimetry DSC has been utilized by many to investigate inclusion complexes in solid state. The melting endotherm of the substrate typically is changed as a result of complexation. The complex formed may have a different melting point, or no melting endotherm because of its amorphous nature. The physical mixture in most cases will still exhibit the melting endotherms of the substrate and the CD (if it is crystalline). In DSC an interaction is indicated by elimination of endothermic peaks, appearance of new peaks, change in peak, shape and its onset, peak temperature, melting point and relative peak area or enthalpy [27].

4.5.5

X-ray powder diffraction X-ray diffractometry is also a useful tool to study complexes in the solid state. The complex should give a different XRD pattern compared to the physical mixture of the host and guest molecules. If the complex formed is crystalline, it is

Advantages of CD complexes With the use of CD complexation techniques certain kinds of improvements are possible in almost every dosage form. Besides oral and injectable formulations, CD inclusion has been shown to improve BA of compounds administered by other routes, including ocular, topical, nasal and rectal routes [32-34]. The complexation is very useful for improving the solubility and stability of Class II (glibenclamide, glimepiride, nimesulide etc.) and Class IV drugs (e.g., furosemide). It is generally believed that the mechanism of BA

4.5.2

Scanning electron microscopy It is used to study the surface morphology as well as the particle size of the complex. The difference in crystallization state of the raw material and the product seen under electron microscope indicates the formation of the inclusion complex even if there is a clear difference in crystallization state of the raw material and product obtained by co-precipitation. 4.6


1261


A. Semalty

enhancement by CD complexation is through solubility and dissolution rate improvement. However, it should be noted that CDs might also alter the lipid barrier of the absorption site, which may contribute to the enhanced drug absorption [35-37]. This effect of CDs on the lipid barrier can be attributed to CDs’ ability to form complexes with membrane components such as cholesterol, PLs and proteins. Another major advantage of CD complexation is the improvement in chemical stability of the guest, for example, resistance to oxidation, photolysis or hydrolysis that is observed. Some important applications of CD complexes particularly applicable for insoluble compounds are summarized here. 4.6.1

Solid preparations

. Oral BA of poor water-soluble drugs can be improved

by enhancement of the dissolution rate and/or apparent solubility (via supersaturation in the gastrointestinal fluids). . Physical stability of compounds in their metastable forms (such as amorphous) can be enhanced by the inhibition or prevention of crystal growth. . Content uniformity of a small amount of a drug in bulky diluents can be ensured by an increase in dispersability and fluidity. . Shelf life of drugs can be extended by increasing their stability. 4.6.2

Liquid preparations

. Solubility and/or stability of the drug in water can

be improved. 4.6.3

Suspensions and emulsions

. Caking,

creaming and phase transitions can be suppressed by the protective sheath of CDs. . Thixotropic nature of suspensions can be controlled. . Physical stability of the dispersed system can be improved. 4.6.4

Semisolid preparations

. Solubilized products can be prepared by freeze-drying

CD complexes if needed for enhanced stability. . Suspensions for parenteral use can be prepared by reduc-

ing the drug to a fine powder containing the CD complex by use of ball milling. Limitations of CD complexation Despite several advantages, the CD complexation is also having some limitations. First, the compound has to be able to form complexes with a selected ligand. For compounds with very limited solubility to start with, the solubility enhancement can be very limited. The second limitation is that for the complexes of Ap type, dilution of a system may still result in precipitation. This is also true for solubilization through combined techniques such as complexation with pH adjustment. Third, the potential toxicity issue, regulatory and quality control issues related to the presence of the ligand may add to complication and cost of the development process. Finally, the complexation efficiency is often rather low, thus relatively large amount of CDs are typically required to achieve desirable solubilization effect [38]. 4.7

Improving the effectiveness of CD complexation Various agents can be added in the complexation systems to enhance the solubilization powder of complexation. It becomes beneficial and/or essential to add polymers for improving the solubility in some cases especially when the CD complexes show an increase in the solubility to certain ceiling levels only (depending upon their phase solubility). Moreover, the polymers may be the part of dosage forms (in general) that may have synergistic effect on solubility. Water-soluble polymers, such as hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP) and high-molecular polyethylene glycols (PEGs), have been shown to enhance the drug dissolution rate of poor water drugs in drug--CD complexes [39,40]. In a study, the dissolution rate of glimepiride--HP-b-CD or glimepiride-SBE-b-CD was significantly higher in the presence of HPMC, PVP and PEG4000 or PEG6000 [39]. The dissolution rate of the drug from these ternary systems was found to be highly dependent on polymer type and concentration. The optimum increase in dissolution rate of glimepiride was observed at a polymer concentration of 5% for PEG4000 or PEG6000 and at 20% for HPMC or PVP. 4.8

. Topical BA can be improved by the enhanced release of

a drug from ointment or suppository bases. . Water-absorbing capacity of oleaginous and water-in-oil

bases can be improved by hydrophilic CDs. 4.6.5

Injectable preparations

. Solubility and/or stability of the drug in water can

be improved. . Drug-induced hemolysis and muscular tissue damage

can be reduced. 1262

Overview of some more studies on CD complexes

4.9

Nair et al. developed the hydroxypropyl-b-CD (HP-b-CD) inclusion complex of acyclovir by the kneading method using drug:hydroxypropyl-b-CD (1:1 mole) for the enhancement its oral BA. The formation of acyclovir--HP-b-CD inclusion complex was confirmed by FTIR, DSC and NMR. The inclusion complex showed rapid and complete release of acyclovir in 30min with greater dissolution efficiency (90.05 ± 2.94%). It was concluded that the inclusion




complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses [41]. Guo et al. studied the dissolution enhancement of cefdinir (CEF) by preparing the binary systems of HP-b-CD with CEF using freeze-drying technique in 1:1 molar ratio. The aqueous solubility of CEF--HP-b-CD inclusion complex was found to be 2.36-fold of pure CEF. The dissolution rate of inclusion complex was found to be superior to CEF alone. The formation of the complex was confirmed b FTIR, DSC and XRD studies [42]. Bhati et al. prepared the binary and ternary systems of b-CD, HPb-CD and PVP for improving the solubility of meloxicam. The complexes were prepared with kneading, co-evaporation and freeze-drying methods. It was observed that the combined use of PVP and CDs resulted in a synergistic effect on increasing the aqueous solubility of meloxicam. The DSC, XRPD and FTIR studies confirmed the strong complexation capacity of CDs with meloxicam [8]. George and Vasudevan studied the effect of 2-hydroxypropyl-b-CDs and b-CDs on its aqueous solubility and dissolution rate. The CD complexes were prepared by physical mixtures, kneading methods and co-precipitation methods and were characterized using DSC and FTIR. The solubility and dissolution rate of meclizine HCl were significantly improved in the complexes [43]. Dua et al. prepared the aceclofenac--b-CD complex to improve the in vitro dissolution of aceclofenac by kneading method in 1:1 and 1:2 M ratio. FTIR and DSC studies indicated no interaction between the drug and b-CD in complexes in solid state. Dissolution was enhanced and the enhancement was attributed to the formation of water-soluble inclusion complexes with b-CD [44]. Swami et al. prepared the complex of domperidone with b-CD and HPC with kneading method and characterized the complexes using DSC, IR and scanning electron microscopy (SEM). It was found that domperidone exhibited better aqueous solubility in presence of both HPC and b-CD [45]. Li et al. prepared the inclusion complex of ofloxacin with b-CD and HP-b-CD and evaluated the complexes using florescence, ultraviolet--visible spectroscopy and NMR spectroscopy in solution. Experimental conditions (including the concentration of various CDs and media acidity) were investigated in detail at room temperature. It was concluded that HP-b-CD exhibited the strongest inclusion properties in acidic media while the b-CD exhibited the strongest inclusion properties in natural media [46]. Sathigari et al. prepared the b-CD, HP-b-CD and RM-bCD complexes of efavirenz (EFV) for improving the solubility and dissolution of EFV. The formation of inclusion complex was confirmed by phase solubility studies in liquid state and X-ray diffraction, DSC and SEM analysis in solid state inclusion complex. It was concluded that the physical and kneaded mixture of EFV with CDs generally provide higher dissolution of EFV. The dissolution of EFV was substantially higher

with HP-b-CD and RM-b-CD inclusion complexes prepared with freeze-drying method. Inclusion complex improved the dissolution rate-limited absorption of EFV [47]. Brewster et al. studied the 2-HP-b-CD and sulfobutylether-b-CD (SBE-b-CD) complex of itraconazole. The complex was characterized for phase solubility, supersaturation testing. The phase solubility study indicated that different profiles were generated as a function of the CD examined and the pH of the complexing medium. It was concluded that hydrophilic CD might be useful as formulation adjuncts in supersaturating drug delivery system [48]. Karathanos et al. prepared the vanillin--b-CD complex using freeze-drying method. Formation of inclusion complex was confirmed by DSC. The DSC studies under oxidation condition indicated that the complex of vanillin with b-CD was protected towards oxidation. The structure of the complex in aqueous solution was established by NMR studies. It was concluded that the complex of a vanillin/b-CD inclusion was more soluble in water than vanillin alone [49]. Chen et al. prepared the inclusion complex of astaxanthin with b-CD. The water solubility of the inclusion complex increased significantly as compared to the drug. Complex formation was confirmed by IR spectroscopy. The stability of inclusion complex against temperature and light was greatly enhanced as compared to that of astaxanthin [7]. Sajeesh et al. developed an oral insulin delivery system based on HP-b-CD--insulin complex encapsulated polymethacrylic acid-chitosan-polymer (polyethylene glycol-polymethacrylene glycol copolymer) PMCP nanoparticles. Free radical polymerization of methacrylic acid in presence of chitosan polymer was used to prepare nonoparticles in solvent/surfactant free medium. HP-b-CD complexed insulin was encapsulated into PMCP nanoparticles by diffusion filling method and their in vitro release profile was evaluated at acidic/alkaline pH. PMCP nanoparticles displayed good insulin encapsulation efficiency; and the release profile was largely dependent on the pH of medium. It was concluded that the CDs complexed insulin encapsulation mucoadhesive nanoparticles might be a good candidate for oral insulin delivery [6]. Gibaud et al. developed melarsoprol--CD complex for improving the tolerability and the BA of melarsoprol. The inclusion complexes were prepared in equimolar ratio with different CDs (b-CD, RM-b-CD and HP-b-CD). Phase solubility analysis showed AL-typed diagram with different CDs. The RM-b-CD showed a pronounced effect on the drug hydrolysis and the dissolution rate of melarsoprol [50]. Zheng et al. studied the effects of three b-CDs (unsubstituted b-CD, HP-b-CD and SBE-b-CD) on the chemical stability and water solubility of quercetin, and also studied the complexation mechanisms of these b-CDs with quercetin. Solubility enhancements of quercetin obtained with the three b-CDs followed the rank order: SBE-b-CD > HP-b-CD > b-CD [51]. Haiyun et al. prepared the solid inclusion complex of rutin with b-CD by coprecipitate method. DSC and XRD studies


1263

A. Semalty

O Phosphatidylcholine

H


Ester bonds

O

P

H

H

O

C1

C2

C

O

O

H

C=O C=O

CH2 OH

+ N (CH3)3

CH2

Polar head group Phosphoester bonds

H

Box indicates glycenol component

(CH2)14 (CH2)7 CH3

CH CH (CH2)7

Fatty acid tail is hydrophobic and would be found on the interior of a lipid membrane

CH3

Figure 3. Chemical structure of phosphatidylcholine.

confirmed the formation of inclusion complex. The spatial configuration of the complex was proposed based on NMR and molecular modeling [28]. 5.

PL complexation

Apart from other methods used for modifying the solubility, the complexation with PLs have been found to show improvement in both absorption as well as permeation of the active constituents [52-54]. Therefore, developing the drugs as lipid complexes (also termed as pharmacosomes) may prove to be a potential approach to improve solubility and permeation and minimize the GI toxicity. Pharmacosomes are defined as colloidal dispersions of drugs covalently bound to lipids, and may exist as ultra-fine vesicular, micellar or hexagonal aggregates, depending on the chemical structure of the drug--lipid complex. Classic reviews have been published on this technique [55-57]. Structures and physicochemical and biological properties of lipids

5.1

Lipids or lecithin or phosphatidylcholine (PC) is the principal molecular building block of cell membranes. It is miscible both in water and in oil/lipid environment and well absorbed orally. PLs (Figures 3 and 4) are small lipid molecules in which the glycerol is bonded only to two fatty acids, instead of three as in triglycerides, with the remaining site occupied by a phosphate group [58]. Commercial grade of PC is a natural mixture of neutral and polar lipids. PC, which is a polar lipid, is present in commercial lecithin in concentrations of 20 -- 90%. Most of the 1264

commercial lecithin products contain about 20% PC. Lecithins containing PC are produced from vegetable, animal and microbial sources (mainly from vegetable sources). Unlike other carriers used in novel drugs delivery systems (NDDS), PLs are natural carriers that also show their own therapeutic benefits. Clinical studies have shown that choline is essential for normal liver function [59] and act as an effective hepatoprotective. In vitro studies have shown that these PLs increase hepatic collagenase activity and may thus help prevent fibrosis and cirrhosis by encouraging collagen breakdown [60]. In addition, PC has demonstrated other protective effects in non-alcoholic fatty liver disorders and protection against various other toxic substances like hepatitis A and B. Thus it helps in protection of liver function [61]. In a study chronic active hepatitis C patients were treated with 3 grams/day of PC in double-blind fashion [62]. The patients taking PC showed significantly reduced symptoms, compared with controls. This hypothesized that PC increases cellular membrane fluidity and repairs the membranes of liver cells. The supplemental choline and PC were found to reduce the muscular hyperactivity of tardive dyskinesia (a neurological disorder, characterized by defective cholinergic nerve activity) by about 50 % [63,64]. The PC supplementation has been reported to help in treatment of Alzheimer’s disease also [65]. It has been suggested that it might have some therapeutic role in some cancers also. It has been shown that excess choline can protect against liver cancer in a mouse model [66]. PC has been used to lower serum cholesterol levels, based on the premise that lecithin cholesterol acyltransferase activity has an important role in the removal of cholesterol from



R1

R1

O CH2

C R2

O

O

O

C

C H P

H2C O

O

+ N

H2 C

-

CH3

CH2

O

R2

O

C

CH3

C H2

O

O C

CH3


O

O CH2

R2

O C

O

H2 C

P

H2C

O

O

O

CH2

O

R2

C H

COO-

O

Phosphatidylserine

C

O

+ NH3

O

C

O C H H2C O

O

C H2

H

P

O

R2

C O

H2C

CH2

C O

OH

HO OH OH

H

Phosphatidylinositol

O

O

H

H

OH

H

Phosphatidylethanolamine

H

O O

O

R1

NH3+

H C

O

O

O

R1

C

H2 C

P

H2C

O

Phosphatidylcholine

R1

O

C H

C H

H2C O

O P

O

H2 C

H2 C C

O

O

H

P O

OH

HC -

CH2 O

O

R3 C

O

O C

R4

O

Diphosphatidylglycerol (cardiolipin)

Figure 4. Chemical structure of some phospholipids. Data taken from [73].

tissues. A few studies have shown reduction in serum cholesterol with PC intake [67]. Selection of drugs for lipid complexation Any drug possessing an active hydrogen atom (--COOH, --OH, --NH2 etc.) can be esterified to the lipid with or without spacer chain. Active hydrogen is a hydrogen atom that has an additional electron in its outer shell, which gives it a negative charge. This extra electron is able to react with other compounds. Carboxylic (--COOH) group bearing drugs can be esterified without any spacer chain. On the other hand if --COOH group is not present (but another active hydrogen atom such as --OH, --NH2 is there), esterification can be done by means of a spacer group (like succinic acid as a spacer arm). Synthesis of such complexes may be guided in such a way that it strongly results in an amphiphilic complex, which will facilitate membrane, tissue or cell wall transfer in the organism [55-57]. Unlike CD complexation, the PL complexation is not governed by geometrical factors (size of drugs and its chain length and molecular weight). The chemical factors are actually decisive in determining the kinds of guest molecules that can interact with the PLs to form inclusion complex. The fact is well supported by the 5.2

studies in which the lipid complexation of proteins like insulin and salmon calcitonin (drugs with high molecular weight and large size or chain length) have been successfully developed and have been reported to improve their BA [68,69]. Thermodynamics of PL complexation Like the CD complexation, the standard free-energy decrease associated with formation of lipid complexes is also owing to a negative standard enthalpy change (DH ) with the inclusion process. In general the PLs show endothermic peaks in the range of 70 -- 100 with DHf about 31 J/g. And this enthalpy is changed when a complex is formed. This interaction between PL and the drug may be due to hydrophobic interaction and/or hydrogen bonding. In general the --OH or --C=O groups (present in the phenol rings) of drug may be involved in hydrogen bonding whereas the aromatic rings may be involved in hydrophobic interaction. In the complex, these interactions yield a new sharp peak in DSC [70-72]. 5.3

Methods of preparation of PL complexes Pharmacosomes can be prepared by various methods. Fundamentally, a drug (bearing active hydrogen group) 5.4


1265

A. Semalty

when reacted with PL in the presence of a suitable organic solvent yields pharmacosomes. The drug and the PC are reacted in 1:1 or 1:2 molar ratios. Some methods described in various studies are discussed here [73]. Solvent evaporation technique In this method PLs and the drug (taken in 1:1 or 1:2 molar ratios) are dissolved in a common organic solvent (e.g., dichloromethane, tetrahydrofuran, methanol etc.) and then the solvent is evaporated under vacuum. The drug if present in salt form is to be converted to acid or base form before adding to the common solvent [74]. The complex is obtained as the dried residues, which are collected and placed in vacuum desiccators.

of a clear mixture. The resultant homogeneous solution is then freeze dried overnight at a condenser temperature of --40 C and under vacuum (10 Pa). The resultant complex is flushed with nitrogen and stored at 4 C. Shi et al. prepared a novel insulin--PL complex by this method [79].


5.4.1

Characterization of PL complexes Apart from the standard methods of solubility determination and the dissolution study the PL complexes are characterized by the following parameters. To confirm the formation of a complex or to study the reciprocal interaction between the drugs and the PLs, the following spectroscopic methods are used [73]. 5.5

Fourier transform infrared spectroscopy The formation of the complex can be confirmed by the IR spectroscopy by comparing the spectrum of the complex with the spectrum of the individual components and their physical mixtures. In most of the cases, the IR spectrum of the complex shows a broad peak for hydroxyl group (indicating the interaction at hydroxyl group) in place of the sharp peak (indicating free hydroxyl group) of -OH group in the drug. The interaction may also be evident in the shifting of C=O stretching band [70-73]. 5.5.1

5.4.2

Supercritical fluid process

The solvent evaporation method is always time-consuming and involves multi-stage processing. Moreover, the method is not very helpful in improving the dissolution of lipid complexes [75]. Parameters related to solid morphology, including the particle size, the crystal habit and crystal pattern, influence the dissolution rate of a compound and thus can significantly affect their BA [76]. So the supercritical fluid (SCF) process may be used to enhance the dissolution of pharmacosomes and to simplify the experimental procedures for preparing complexes. Supercritical anti solvent process (SAS) is one of the SCF technologies that are becoming a promising technique to produce micronic and submicronic particles with controlled size and size distribution. The process is characterized by very mild conditions of temperature, and smaller particles can be obtained depending on the drug and process conditions when compared to the common industrial comminution techniques like jet milling, liquid antisolvent precipitation and crystallization [77,78]. Particle size is particularly related to the dissolution of drugs and thus can significantly affect their BA. So the SAS process may increase the dissolution of pharmacosomes. Two different SCF technologies, gas antisolvent (GAS) and solution enhanced dispersion by SCF (SEDS), belonging to SAS process, were used by Li et al. [75] for preparation of PL complexes of puerarin. In the GAS process, mass transfer typically occurs by the mechanism of convection and molecular diffusion, leading to relatively small supersaturation for many solutes. In the SEDS process, premixing is created between a fresh liquid solution and SC--CO2, which produces high supersaturation and predominantly occurs within the nozzle mixing chamber. This process features a highly turbulent flow of solvent and CO2, leading to a very fast mixing or dispersion. Using this technique, it is possible to control the size, shape and morphology of the material of interest. Anhydrous co-solvent lyophilization method In this method the drug and PLs are co-dissolved in a little (about 1 ml) organic solvent/(s) (like dimethyl sulfoxide and/ or glacial acetic acid) with gentle agitation until the formation 5.4.3

1266

13

C-NMR In the 13C-NMR spectrum of (+)-catechin and its stoichiometric complex with distearoylphosphatidylcholine, particularly when recorded in C6D6 (solvent-deuteriated benzene) at room temperature, all the flavonoid carbons are practically invisible. The signals corresponding to the glycerol and choline portion of the lipid (between 60 and 80 ppm) are broadened and some are shifted, while most of the resonances of fatty acid chains retain their original sharp line shape. 5.5.2

1

H-NMR In the NMR spectra of the complex, all the signals of protons of PLs generally show the broadening with upfield shifting of choline of trimethylammonium group (N--(CH3)3). Therefore, the complex shows a marked change of the 1H-NMR signal corresponding to the atoms involved in the formation of the complex [55,73]. The PL complex with catechin revealed similar H--NMR except the proton of phenolic --OH, which shifted downfield indicating the interaction of PL with phenolic --OH of catechin [72]. 5.5.3

Surface morphology Surface morphology of the pharmacosome can be studied and observed with SEM or transmission electron microscopy (TEM). The surface morphology as well as the particle size is detected by SEM. The shape and size of the prepared complexes may be affected by the process variables like speed of rotation, vacuum applied or the method used. The purity grade of PL also plays an important role in governing the shape, size and stability of the pharmacosomes. Using low 5.5.4



purity grades of lipids for PL complex preparation yields a greasy product, which in turn results in PL complexes of large aggregates and sticky nature. On the other hand very high purity grades (> 90 %) are prone to oxidative degradation, and hence adversely affect the stability of PL complexes. In general PLs of about 80% purity have been used in PL complex preparation in most studies. Differential scanning calorimetry DSC is a fast and reliable method to screen drug--excipient compatibility and provides maximum information about the possible interactions. In DSC, an interaction is concluded by elimination of endothermic peak(s), appearance of new peak(s) and change in peak shape and its onset, peak temperature/melting point and relative peak area or enthalpy. As discussed in thermodynamics the reduced enthalpy, disappearance of individual endothermic peaks of PLs and drugs and appearance of a new endothermic peak is generally considered to be the confirmation of complexation [70-73].


5.5.5

fluidity depends upon the phase transition temperature of the drug--lipid complex, but it does not affect release rate; the stability of the complex depends on the physicochemical properties of the drug--lipid complex; the rate of degradation of the complex into active drug molecule following absorption depends to a great extent on the size and functional groups of drug molecule, the chain length of the lipids and the spacer; these complexes can be given orally, topically, extra- or intravascularly. Limitations of PL complexes The use of lipid complexes for improving solubility may be limited due to the incompatibility with the PL. The presence of PL may sometime make the system more hygroscopic, if the higher purity grades of PLs are used. Second, all drugs cannot form the complexes with the PLs. Requisite criteria are the presence of free hydroxyl group (for interaction with PLs) in the structure of the drug. 5.7

Improving the effectiveness of PL complexation The use of advanced new techniques like super critical fluid and lyophilization methods can improve the effectiveness of complexation. Moreover, the use of high purity grades of PLs with advanced and effective processing and packaging of the product may result in stable lipid complexes with better shelf lives. 5.8

5.5.6

X-ray powder diffraction

To check whether the changes in the diclofenac crystal morphology correspond to a polymorphic transition and to study the solid state of diclofenac PL complex, XRPD analyses are conducted [73]. From these patterns, the degree of crystallinity could be evaluated using the relative integrated intensity of reflection peaks in the given range of reflecting angle, 2q. The value of 2q means the diffraction angle of ray beams. The integrated intensity is given by the AUC of the XRPD patterns, and it stands for the characteristics of the specimen. The amorphization of drug in the complex is indicated by the reduced intensity/disappearance of crystalline peaks of drug and PLs. From comparative study of PL and CD complexes, it is observed that in case of the former the amorphization is always greater as compared to the latter. The CD complexes show many crystalline peaks but the PL complex show just one large diffused peak with reduced intensity. Significant change of its X-ray diffraction in PL complex might be due to chemical bonding between drug and the PLs, which was not otherwise present in other lipid based systems like liposomes. Various studies done with the PL complexes of insulin, salmon calcitonin, baicalein, chrysophanol and catechin and so on support this inference [68-73]. Advantages of PL complexes The pharmacosomes are zwitter ionic, amphiphilic, stoichiometric complexes of polyphenolic compounds with PLs. Unlike other lipid based delivery system, pharmacosomes or the lipid complexes show better results, which are as follows [57,73]. High entrapment efficiency: entrapment efficiency is independent of entrapped volume and drug-bilayer interactions (unlike liposomes); no need of following the processes (like removing the free, unentrapped drug from the formulation), which are generally tedious and time-consuming; no loss of drug due to leakage caused by bonding; membrane 5.6

Overview of some more studies on PL complexes The lipid complexes have successfully improved the therapeutic performance of various drugs like NSAIDs, hormones, phytoconstituents like flavonoids and so on. Various studies focusing on the use of PL complexes in improving solubility, dissolution and BA are summarized as follows. Bhattacharyya et al. prepared the lipid complexes of gallic acid and studied the effect of PL complexation on carbon tetrachloride (CCl4)-induced oxidative damage in rat liver. The complex significantly reduced the hepatic marker enzymes in rat serum and restored the antioxidant enzyme levels with respect to CCl4-induced group. Also, the complex improved the pharmacokinetics of gallic acid by increasing the relative BA and elimination half-life [80]. Singh et al. prepared the PL complexes of two phytoconstituents baicalein and chrysophanol in two different studies. PL complexes were prepared with solvent evaporation technique taking 1:1 ratio of drug:PC. The complex formation was confirmed by FTIR, DSC and XRPD studies. The solubility and the dissolution was improved very significantly in the complexes [70,71]. Rawat et al. prepared the silymarin--PL complexes with solvent evaporation technique. The formation of the complex with PL in the solid state was confirmed by FTIR, DSC and XRPD. Amorphization of the drug in the complex was confirmed by XRPD [81]. Semalty et al. prepared the catechin--PL complexes to improve the dissolution of catechin. The prepared PL complex 5.9


1267

A. Semalty

Table 4. Critical and meta-analysis of PL and BCD complexation for some drugs. Drug

Properties

PL complex

BCD complex

Ref.

Diclofenac

DSC

The complex exhibited a single sharp new peak The complex showed only a unique large diffraction peak (without the presence of the sharp and intense peaks of crystalline diclofenac) Water solubility increased 2-fold

The characteristic peaks of the drug were not visible The characteristic peaks of the drug were not visible

[90,94]

XRD


Solubility Dissolution

Nimesulide

DSC

XRD

Solubility Dissolution Naringenin

DSC XRD

Quercetin

Solubility Dissolution DSC

XRD

Solubility

Rutin

Dissolution DSC

XRD

Solubility Dissolution

Pharmacosomes showed 87.8% while the free diclofenac acid showed a total of only 60.4% drug release at the end of 10 h The complex exhibited a single sharp new peak The complex showed only a unique large diffraction peak (without the presence of the sharp and intense peaks of crystalline nimesulide) Water solubility increased 12-fold; n octanol solubility increased 8-fold 92.76% in vitro drug release in 24 h The complex showed new peaks with reduced onset temp The complex showed a broad peak similar to PL Water solubility increased 2-fold About 100% release in 8 h The complex showed a complete disappearance of the melting endothermic peaks with reduced enthalpy and melting points The complex showed large diffraction peaks in which it was no longer possible to distinguish the characteristic peaks of the drug Aqueous solubility of quercetin improved by 12-fold in the complex -The complex showed complete disappearance of the endothermic peaks of the individual component and exhibited a broad new peak at about 71.14 C Unlike the free rutin, which showed a total of 30.05 and 54.04% drug release, the rutin complex showed 60.05 and 80.89% drug release at the end of 24 h Water solubility increased 15-fold Unlike the free rutin, which showed a total of 30.05 and 54.04% drug release, the rutin complex showed 60.05 and 80.89% drug release at the end of 24 h

The solubility of the drug increased linearly with the increase of b-CD concentration A 20-fold increase in dissolution was observed with the freeze-dried inclusion complex The crystalline peaks of the drug and of the BCD were reduced (in the same position or temperature) or disappeared completely b-CD complex exhibited disappearance and reduction in the intensity of large diffraction peaks

[95,96]

Water solubility increased 12-fold The complexes released the complete drug in 30 -- 40 min The complex exhibited disappearance of the peak corresponding to drug The complex exhibited disappearance and reduction in the intensity of large diffraction peaks Water solubility increased 2-fold 98 -- 100% drug release in 1 h Reduced intensity peaks with absence of CD peak at 220

[87,20]

[82,21]

--

Water solubility increased 4.6-fold -Sharp and clear new peak for the complex

[83,28]

The complex showed unique XRD pattern

---

BCD: Beta cyclo dextrin; CD: Cyclodextrin; DSC: Differential scanning calorimetry; PL: Phospholipid; XRD: X-ray diffractometry.

showed high drug content (99.4% w/w) and improved lipid solubility (0.79 -- 1.97 mg/ml). FTIR, NMR, DSC and XRPD data confirmed the formation of PL complex. Unlike the free catechin, catechin complex showed a sustained release over the 1268

24 h study. Catechin--PL complex showed slightly better antioxidant activity than that of catechin at all dose levels [72]. Singh et al. in three different studies prepared the PL complexes of three flavones, namely, quercetin, rutin and




emodin. In all the studies PC complex formation was confirmed by FTIR, DSC and XRPD. The water solubility of quercetin was improved 12-fold (from 3.44 µg/ml to 36.81 µg/ml) in the prepared complex. The water and noctanol solubility of rutin was improved from 2.88 to 45.71 µg/ml and from 68.17 to 245.18 µg/ml, respectively, in the complex. The improved dissolution was shown by the rutin--PL complex at different pH buffers. The water and n octanol solubility of emodin was improved from 2.25 to 9.97 and 53.45 to 77.62 µg/ml, respectively, in the prepared complex. Moreover, the in vitro antioxidant activity of the flavones was maintained even after being complexed with the PL [82-84]. Singh et al. prepared the PC complexes of gallic acid to improve the BA and prolong its duration. The PL complex of gallic acid was found to be fluffy and porous with rough surface morphology. FTIR, DSC and XRPD data confirmed the complex formation. It was found that 89.1% of gallic acid was encapsulated in the PL complex. A controlled release pattern was shown by the complex (which showed continuous release up to 93% of gallic acid) at the end of 24 h in comparison to free gallic acid (which showed 81.91% burst release in just 0.5 h) [85]. Wu et al. developed a new PL complex self-emulsifying drug delivery system (PC-SEDDS) to enhance BA of oral etoposide, which has poor water solubility. The etoposide--PL complex was prepared by reacting etoposide and PL in tetrahydrofuran and characterized by DSC. It was concluded that PC-SEDDS proved to be a potential system for delivering orally administered hydrophobic compounds, including etoposide [86]. Semalty et al. prepared PL complex of naringenin (a flavonoid obtained from citrus fruit and possessing anti-inflammatory, anti-carcinogenic and anti-tumor effects) to improve the BA and prolong its duration of action in the body system. FTIR, NMR, DSC and XRPD data confirmed the formation of PL complex. Water solubility of naringenin improved from 43.83 to 79.31 µg/ml in the prepared complex. Unlike the free naringenin (which showed a total of only 27% drug release at the end of 10 h), naringenin complex showed 99.80% release at the end of 10 h of dissolution study [87]. Fricker et al. summarized particular features of commonly used PLs and their application spectrum within oral drug formulation and elucidate current strategies to improve BA and disposition of orally administered drugs. The advantages of PLs have also been focused on [88]. Semalty et al. prepared a PL complex of aspirin and diclofenac to improve the solubility (and hence the BA) and minimize the GI irritation. Its complexes with soya--PL 80% (in 1:1 molar ratio) were prepared in an organic solvent and evaluated for solubility, drug content, SEM, FTIR spectra, X-ray diffraction, DSC and in vitro dissolution study. It was concluded that the PL complex of aspirin and diclofenac may be of potential use for improving the solubility and hence its BA [89,90].

6.

Expert opinion

In order to improve solubility and dissolution profile of a BCS Class II and Class IV drugs various methods can be adopted. Various techniques like solid dispersion, solvent deposition, micronization and so on have been investigated for resolving the solubility issue in pharmaceutical product development. Each of these techniques has its own merits and some demerits. Out of these, complexation techniques have been employed more precisely to improve the solubility and the dissolution of poorly water-soluble drugs. The CD complexation and PL complexation are among the exhaustively investigated methods. Various studies have reported that the CDs and PL complexation may be the potential approaches to improve the dissolution, absorption and the BA of the drugs. Both the techniques can develop a drug in the form a complex with better biopharmaceutical properties. But the eligibility criterion for the CD complex is rather more geometric than the chemical as compared to the PL complexation. On the other hand the PL complexes may also improve the lipid solubility or the permeability of BCS Class IV drugs leading to improved BA of permeability rate limited drugs also. Both kinds of complexation lead to the amorphization of drug in the complex. But it is also evident that the amorphization (leading to improved solubility) is strong in PL complexes as compared to the CD complexes. Upon the critical and meta-analysis of both kinds of complexation, taking examples of a few drugs (Table 4), it was evident that the complexation show distinguished characteristic results for DSC, XRD, solubility and dissolution study. But it is equally important to take a suitable drug with certain definite molar ratio for a particular kind of complex preparation. The selection of a cost-effective method is also a critical factor. A formulation scientist can make a better judgment in choosing a particular kind of complexation with reference to cost, stability and effectiveness of the complexes. It can be concluded that the CD and PL complexation of drugs may be a very promising approach for improving the BA of BCS Class II and Class IV drugs.

Declaration of interest A part of the work was supported by government of India, UGC research grant 37 -- 643/2009, provided for the research work. Analytical instrumental facilities were provided by the UGC-DAE Consortium for Scientific Research, Indore (MP), India. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


1269

A. Semalty

Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.


2.

3.

4.

5.

6.

Semalty A, Semalty M, Rawat MSM. Essentials of pharmaceutical technology. 1st edition. Pharma Med Press; Hyderabad, India: 2011. p. 4-5 Moneghini M, Kikig I, Perissutti B, et al. Characterization of nimesulide-b-cyclodextrin system prepared by supercritical fluid impregnation. Eur J Pharm Bioparm 2004;58:637-44 Pralhad T, Kumar R. Study of freezedried quercetin-cyclodextrin binary system by DSC, FTIR, X-ray diffraction and SEM analysis. J Pharm Biomed Anal 2004;34:333-9 Babu RJ, Pandit JK. Effect of cyclodextrin on the complexation and transdermal delivery of bupranolol through rat skin. Int J Pharm 2004;271:155-65 Rawat S, Jain SK. Solubility enhancement of celecoxib using betacyclodextrin inclusion complexes. Eur J Pharm Biopharm 2004;51:263-7 Sajeesh S, Sharma CP. Cyclodextrin -insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery. Int J Pharm 2006;325:147-54

7.

Chen X, Chen R, Guo Z, et al. The preparation and stability of the inclusion complex of astaxanthin with beta-CD. Food Chem 2007;101:1580-4

8.

Bhati LK, Tiwari G, Tiwari R, et al. Enhancement of complexation efficiency of meloxicam using binary and ternary solid systems: formulation considerations. Am J Drug Discov Dev 2012;2(1):17-31

9.

10.

Connors KA. Complex formation. In: Gebbaro AR, Remington’s pharmaceutical sciences. 18th edition. Mack Publishing Co, PA, USA; 1990 Magnusdottir M, Lofisson T. Cyclodextrins. J Incl Phenom Macrocycl Chem 2002;44:213-18

11.

Rasheed A, Kumar A. Cyclodextrin as drug carrier molecule. Sci Pharm 2008;76:567-98

12.

Loftsson T, Brewsteer ME, Masson M. Role of cyclodextrin in improving oral

1270

..

drug delivery. Am J Drug Deliv 2004;2(4):261-75 Exhaustive review on the role of cyclodextrin in oral drug delivery.

13.

Irie T, Uekama K. Pharmaceutical application of cyclodextrin, toxicological issues and safety evaluation. J Pharm Sci 1997;85:147-62

14.

Del VE. Cyclodextrins and their uses: a review. Process Biochem 2004;39:1033-46

15.

Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutical classification system: the central role of dose/solubility ratio. Pharm Res 2003;20:1917

16.

Vekama K. Design and evaluation of cyclodextrin based drug formulation. Chem Pharm Bull 2004;52:900-15

17.

Wei QT, Wen H. Applications of complexation in the formulation of insoluble compounds. In: Liu R, editor. Water insoluble drug formulation. 2nd edition. CRC Press; London: 2008. p. 133-59

18.

Szejtli J. Medicinal applications of cyclodextrins. Med Res Rev 1994;14:353-86

19.

Connors KA. The stability of cyclodextrin complexes in solution. Chem Rev 1997;97:1325-57

20.

Semalty A, Tanwar YS, Semalty M. Preparation and characterization of cyclodextrin inclusion complex of naringenin and critical comparison with phospholipid complexation for improving solubility and dissolution. J Thermal Anal Calorim 2014;115:2471-8 Research article focusing critical comparison of two complexation techniques.

.

21.

22.

23.

Borghetti GS, Lula IS, Sinisterra RD, et al. Quercetin/beta-cyclodextrin solid complexes prepared in aqueous solution followed by spray-drying or by physical mixture. AAPS PharmSciTech 2009;10(1):235-42 Patil JS, Kadam DV, Marapur SC, et al. Inclusion complex system; a novel technique to improve the solubility and bioavailability of poorly soluble drugs. Int J Pharm Sci 2010;2(2):29-32 Saravana KK, Sushma M, Prasanna RY. Dissolution enhancement of poorly soluble drugs by using complexation Expert Opin. Drug Deliv. (2014) 11(8)

technique -- a review. J Pharm Sci Res 2013;5(5):120-4 24.

Friedrich H, Nada A, Bodmier R. Solid state and dissolution rate characterization of co-ground mixtures of nifedipine and hydrophilic carriers. Drug Dev Ind Pharm 2005;31:719-28

25.

Sauceau M, Rodier E, Fages J. The preparation of inclusion complex of piroxicam with cyclodextrin by using supercritical carbon dioxide. J Supercritical Fluids 2008;47(2):326-32

26.

Sunkara G, Kompella UB. Drug delivery application of supercritical fluid technology. Drug Dev Technol 2002;2:44-50

27.

Semalty M, Panchpuri M, Singh D, et al. Cyclodextrin inclusion complex of racecadotril: effect of drug-beta-cyclodextrin ratio and the method of complexation. Curr Drug Discov Tech 2014; In press

28.

Haiyun D, Jianbin C, Guomei Z, et al. Preparation and spectral investigation on inclusion complex of beta-cyclodextrin with rutin. Spectrochim Acta Part A 2003;59:3421-9

29.

Ficarra R, Tommasini S, Raneri D, et al. Study of flavonoids/beta-cyclodextrins inclusion complexes by NMR, FTIR, DSC, x-ray investigation. J Pharm Biomed Anal 2002;29:1005-14

30.

Lantz AW, Rodriguez MA, Wetterer SM, et al. Estimation of association constants between oral malodor components and various native and derivatized cyclodextrins. Anal Chim Acta 2006;557:184-90

31.

Rajendrakumar K, Madhusudan S, Pralhad T. Cyclodextrin complexes of valdecoxib: properties and antiinflammatory activity in rat. Eur J Pharm Biopharm 2005;60:39-46

32.

Loftsson T, Leeves N, Sigurjonsdottir JF, et al. Sustained drug delivery system based on a cationic polymer and an anionic drug/cyclodextrin complex. Pharmazie 2001;56:746-7

33.

Rode T, Frauen M, Muller BW, et al. Complex formation of sericoside with hydrophilic cyclodextrins: improvement of solubility and skin penetration in topical emulsion based formulations. Eur J Pharm Biopharm 2003;55:191-8


34.

Loftsson T, Jarho P, Masson M, et al. Cyclodextrin in drug delivery. Expert Opin Drug Deliv 2005;2:335-51

35.

Monnaert V, Betbeder D, Fenart L, et al. Effects of gamma- and hydroxypropylgamma- cyclodextrins on the transport of doxorubicin across an in vitro model of blood-brain barrier. J Pharmacol Exp Ther 2004;311:1115-20


36.

37.

38.

39.

40.

41.

42.

43.

44.

Monnaert V, Tilloy S, Bricout H, et al. Behavior of alpha-, beta-, and gammacyclodextrins and their derivatives on an in vitro model of blood-brain barrier. J Pharmacol Exp Ther 2004;310:745-51 Tilloy S, Monnaert V, Fenart L, et al. Methylated b-cyclodextrin as P-gp modulators for deliverance of doxorubicin across an in vitro model of blood--brain barrier. Bioorg Med Chem Lett 2006;16(8):2154-7 Loftsson T, Masson M, Sigurjonsdottir JF. Methods to enhance the complexation efficiency of cyclodextrins. STP Pharm Sci 1999;9:237-42 Ammar HO, Salama HA, Ghorab M, et al. Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy. Int J Pharm 2006;320:53-7 Cao F, Guo J, Ping Q. The physicochemical characteristics of freeze-dried scutellarin-cyclodextrin tetracomponent complexes. Drug Dev Ind Pharm 2005;31:747-56 Nair AB, Attimarad M, Al-Dhubiab BE, et al. Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-b-cyclodextrin. Drug Deliv 2013. [Epub ahead of print] Guo B, Zhong S, Li N, et al. Dissolution enhancement of cefdinir with hydroxypropyl-beta-cyclodextrin. Drug Dev Ind Pharm 2013;39(11):1638-43 George S, Vasudevan D. Studies on the preparation, characterization, and solubility of 2-HP-beta-cyclodextrinmeclizine HCl inclusion complexes. J Young Pharm 2012;4(4):220-7 Dua K, Pabreja K, Ramana MV, et al. Dissolution behavior of beta-cyclodextrin molecular inclusion complexes of aceclofenac. J Pharm Bioallied Sci 2011;3(3):417-25

45.

46.

47.

48.

49.

50.

51.

52.

53.

Swami G, Koshy MK, Pandey M, et al. Preparation and characterization of domperidone-beta-CD complexes prepared by kneading method. Int J Adv Pharm Sci 2010;1:68-74 Li J, Zhang X. Preparation and characterization of the inclusion complex of ofloxacin with beta-CD and HP-beta-CD. J Incl Phenom Macroc Chem 2010;69:173-9 Sathigri S, Chandha G, Lee YHP, et al. Physicochemical characterization of efavirenze -- cyclodextrin inclusion complex. AAPS Pharm Sci Tech 2008;10(1):81-7 Brewster ME, Vandecruys R, Peeter J, et al. Comparative interaction of 2hydroxypropyl - beta-cyclodextrin & sulfobutylether - beta-cyclodextrin with itraconazole: phase -- solubility behavior & stabilization of supersaturated drug solutions. Eur J Pharm Sciences 2008;34:94-103 Karathanos VT, Mourtzinos I, Yankopoular K, et al. Study of the solubility, antioxidant activity & structure of inclusion complex of vanillin with beta-cyclodextrin. Food Chem 2007;101:652-8 Gibaud S, Zirar SB, Mutzeahard P, et al. Melarsoprol- cyclodextrins inclusion complexes. Int J Pharm 2005;306:107-21 Zheng Y, Haworth IS, Zuo Z, et al. Physicochemical and structural characterization of quercetin-b-cyclodextrin complexes. J Pharm Sci 2005;94(5):1079-89 Mukherjee PK, Maiti K, Kumar V. Value added drug delivery systems with botanicals: approach for dosage development from natural resources. Pharm Rev 2007;6:57-60 Samuni A, Chong PLG, Barenholz Y. Physical and chemical modifications of adriamycirdron complex by phospholipid bilayers. Cancer Res 1986;46:594-9

54.

Tanhuanpaa K, Cheng KH, Anttonen K. Characteristics of pyrene phospholipid/gcyclodextrin complex. Biophys J 2001;81(9):1501-10

55.

Bombardelli E, Spelta M. Phospholipid-polyphenol complexes: a new concept in skin care ingredients. Cosm Toil 1991;106(3):69-76

56.

Vaizoglu O, Speiser PP. Pharmacosomes: a novel drug delivery system. Acta Pharm Suec 1986;23:163-72


57.

Biju SS, Talegaonkar S, Mishra PR, et al. Vesicular systems: an overview. Indian J Pharm Sci 2006;68:141-53

58.

Semalty A, Semalty M, Singh R, et al. Phytosome in herbal drug delivery: a review. Indian Drugs 2006;43:937-46

59.

Canty DJ, Zeisel SH. Lecithin and choline in human health and disease. Nutr Rev 1994;52:327-39

60.

Lieber CS, De Carl LM, Mak KM. Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin. Hepatology 1990;12:1390-8

61.

Lieber CS, Leo MA, Aleynik SI. Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon. Alcohol Clin Exp Res 1997;21:375-9

62.

Kosina F, Budka K, Kolouch Z. Essential cholinephospholipids in the treatment of virus hepatitis. Cas Lek Cesk 1981;120:957-60

63.

Gelenberg AJ, Dorer DJ, Wojcik JD. A crossover study of lecithin treatment of tardive dyskinesia. J Clin Psychiatry 1990;51:149-53

64.

Growdon JH, Gelenberg AJ, Doller J. Lecithin can suppress tardive dyskinesia. New Eng J Med 1978;298:1029-30

65.

Little A, Levy R, Chuaqui-Kidd P. Double-blind, placebo-controlled trial of high-dose lecithin in Alzheimer’s disease. J Neur Neurosurg Psychol 1985;48:736-42

66.

Hirsch MJ, Growdon JH, Wurtman RJ. Relations between dietary choline or lecithin intake, serum choline levels, and various metabolic indices. Metabolism 1978;27:953-60

67.

Hanin I, Ansell GB. Lecithin. Technological, biological and therapeutic aspects. Plenum Press; New York and London: 1987

68.

Cui F, Shi K, Zhang L, et al. Biodegradable nanoparticles loaded with insulin-phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J Control Release 2006;114:242-50

69.

Yoo HS, Park TG. Biodegradable nanoparticles containing protein-fatty acid complex for oral delivery of salmon calcitonin. J Pharm Sci 2003;93:488-95

70.

Singh D, Thakur B, Semalty M, et al. Baicalein-phospholipid complex: a novel drug delivery technology for

1271

A. Semalty


phytotherapeutics. Curr Drug Discov Technol 2013;10(3):224-32 71.

Singh D, Rawat MSM, Semalty A, et al. Chrysophanol--phospholipid complex. J Therm Anal Calorim 2013;111(3):2069-77

72.

Semalty A, Semalty M, Singh D, et al. Phyto-phospholipid complex of catechin in value added herbal drug delivery. J Incl Phenom Macrocycl Chem 2012;73(1-4):377-86

73.

..

74.

75.

76.

77.

78.

79.

1272

Semalty A, Semalty M, Rawat BS, et al. Pharmacosomes: the lipid based novel drug delivery system. Exp Opin Drug Deliv 2009;6:599-612 Provides the state of the art of phospholipid complexation of synthetic drugs. Khazaeinia T, Jamali F. A comparison of gastrointestinal permeability induced by diclofenacphospholipid complex with diclofenac acid and its sodium salt. J Pharm Pharm Sci 2003;6(3):352-9 Li Y, Yang DJ, Chen SL, et al. Comparative physicochemical characterization of phospholipids complex of puerarin formulated by conventional and supercritical methods. Pharm Res 2007;25:563-77 Perrut M, Jung J, Leboeuf F. Enhancement of dissolution rate of polysoluble active ingredients by supercritical fluid processes. Part I: micronization of neat particles. Int J Pharm 2005;288:3-10 Reverchon E, Della Porta G, Failivene MG. Progress parameters and morphology in amoxicillin micro and submicro particles generation by supercritical antisolvent precipitation. J Supercrit Fluids 2000;17:239-48 Warwick B, Dehghani F, Foster NR, et al. Synthesis, purification, and micronization of pharmaceuticals using the gas antisolvent technique. Ind Eng Chem Res 2000;39:4571-3 Shi K, Cui F, Yu Y, et al. Preparation and characterization of a novel insulinphospholipid complex. Asian J Pharm Sci 2006;1(3-4):168-74

80.

81.

Bhattacharyya S, Ahammed SM, Saha BP, et al. The gallic acidphospholipid complex improved the antioxidant potential of gallic acid by enhancing its bioavailability. AAPS PharmSciTech 2013;14(3):1025-33 Rawat DS, Thakur BK, Semalty M, et al. Silymarin-phospholipid complexes: a drug delivery system in NDDS. Univ J Phytochem Ayurvedic Hights 2012;1(12):4-13

improved drug delivery. Int J Pharm Sci Nanotechnol 2010;3:946-53 90.

Semalty A, Semalty M, Singh D, et al. Development and physicochemical evaluation of pharmacosomes of diclofenac. Acta Pharm 2009;59:335-44

91.

Semalty A, Semalty M, Rawat BS, et al. Development and evaluation of pharmacosomes of aceclofenac. Indian J Pharm Sci 2010;72:571-5

92.

Semalty A, Semalty M, Singh D, et al. The phyto-phospholipid complexesphytosomes: a potential therapeutic approach for herbal hepatoprotective drug delivery. Pharmacogenetics Rev 2007;1:369-74

93.

Semalty A, Semalty M, Rawat MSM, et al. Supramolecular phospholipidspolyphenolic interactions: the PHYTOSOME strategy to improve the bioavailability of phytochemicals. Fitoterapia 2010;81:306-14 Provides the state of the art of phyto-phospholipid complexation in improving solubility, dissolution and bioavailability of herbal drugs.

82.

Singh D, Rawat MSM, Semalty A, et al. Quercetin-phospholipid complex: an amorphous pharmaceutical system in herbal drug delivery. Curr Drug Discov Tech 2012;9(1):17-24

83.

Singh D, Rawat MSM, Semalty A, et al. Rutin-phospholipid complex: an innovative technique in novel drug delivery system- NDDS. Curr Drug Deliv 2012;9(3):305-14

84.

Singh D, Rawat MSM, Semalty A, et al. Emodin-phospholipid complex: a potential of Herbal drug in the novel drug delivery system. J Therm Anal Calorim 2012;108(1):289-98

94.

85.

Singh D, Rawat MSM, Semalty A, et al. Gallic acid-phospholipid complex: drug incorporation and physicochemical characterization. Lett Drug Des Discov 2011;8(3):284-91

Manca ML, Zaru M, Ennas G, et al. Diclofenac-beta-cyclodextrin binary systems: physicochemical characterization and in vitro dissolution and diffusion studies. AAPS Pharm Sci Tech 2005;6:3

95.

86.

Wu Z, Guo L, Deng L. Preparation and evaluation of a self-emulsifying drug delivery system of etoposide-phospholipid complex. Drug Dev Ind Pharm 2011;37:103-12

Semalty A, Tanwar YS. Nimesulide-phosphatidylcholine complex for improvement of solubility and dissolution. Am J Drug Discov Dev 2014

96.

87.

Semalty A, Semalty M, Singh D, et al. Preparation and characterization of phospholipid complexes of naringenin for effective drug delivery. J Incl Phenom Macrocycl Chem 2010;67:253-60

Semalty A, Tanwar YS. Preparation and characterization of cyclodextrin inclusion complexes for improving solubility and dissolution of nimesulide. World J Pharm Sci 2014;2(1):72-8

88.

Fricker G, Kromp T, Wendel A, et al. Phospholipids and lipid- based formulations in oral drug delivery. Pharm Res 2010;27:1469-86

89.

Semalty M, Semalty A, Singh D, et al. Development and characterization of aspirin-phospholipid complex for


.

Affiliation Ajay Semalty M PHARM MBA Professor, H.N.B. Garhwal University Srinagar (Garhwal), Department of Pharmaceutical Sciences, Chauras Campus, Chauras, Srinagar (Garhwal), 246174, India E-mail: [email protected]

Effect of cyclodextrin complexation on phenylpropanoids' solubility and antioxidant activity.

Aripiprazole-cyclodextrin binary systems for dissolution enhancement: effect of preparation technique, cyclodextrin type and molar ratio.

Complexation of carbendazim with hydroxypropyl-β-cyclodextrin to improve solubility and fungicidal activity.

The influence of beta-cyclodextrin on the solubility and dissolution rate of paracetamol solid dispersions.

methyl β-cyclodextrin inclusion complexes: physicochemical characterization, solubility, dissolution, and biological studies.

A Critical Appraisal of Solubility Enhancement Techniques of Polyphenols.

Enhancement of solubility and dissolution of cilostazol by solid dispersion technique.

Complexation of steroid hormones with cyclodextrin derivatives: substituent effects of the guest molecule on solubility and stability in aqueous solution.

Enhancement of specific biological activity of dipyridamole by complexation with beta-cyclodextrin.

Intermolecular complexation of low-molecular-weight succinoglycans directs solubility enhancement of pindolol.

Design of a novel crosslinked HEC-PAA porous hydrogel composite for dissolution rate and solubility enhancement of efavirenz.

Influence of excipients on solubility and dissolution of pharmaceuticals.

Enhancement of solubility, dissolution release profile and reduction in ulcerogenicity of piroxicam by inclusion complex with skimmed milk.

Improving permeability and oral absorption of mangiferin by phospholipid complexation.

Synthesis, cytotoxicity, and phase-solubility study of cyclodextrin click clusters.

Nanoassemblies driven by cyclodextrin-based inclusion complexation.

Baicalein-nicotinamide cocrystal with enhanced solubility, dissolution, and oral bioavailability.

Synthetic hydroxyapatite-solubility product and stoichiometry of dissolution.

Dissolution and Solubility Enhancement of the Highly Lipophilic Drug Phenytoin via Interaction with Poly(N-isopropylacrylamide-co-vinylpyrrolidone) Excipients.

Artemether-Soluplus Hot-Melt Extrudate Solid Dispersion Systems for Solubility and Dissolution Rate Enhancement with Amorphous State Characteristics.

HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability.

Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs: Investigation Into Celecoxib Incorporation and Solubility-In Vitro Permeability Enhancement.

Dissolution Rate Enhancement, Design and Development of Buccal Drug Delivery of Darifenacin Hydroxypropyl β-Cyclodextrin Inclusion Complexes.

Posttraumatic stress disorder in critical illness survivors: a metaanalysis.