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Liquid crystalline phase as a probe for crystal engineering of lactose: Carrier for pulmonary drug delivery
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Sharvil S. Patil a,⇑, Kakasaheb R. Mahadik a, Anant R. Paradkar b a b
Bharati Vidyapeeth University, Poona College of Pharmacy, Department of Pharmaceutics, Erandwane, Pune 411038, India Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford BD7 1DP, UK
a r t i c l e
i n f o
Article history: Received 1 August 2014 Received in revised form 14 November 2014 Accepted 14 November 2014 Available online xxxx Keywords: Cubic phase Lactose monohydrate Cascade impactor Salbutamol sulfate Glyceryl monooleate
a b s t r a c t The current work was undertaken to assess suitability of liquid crystalline phase for engineering of lactose crystals and their utility as a carrier in dry powder inhalation formulations. Saturated lactose solution was poured in molten glyceryl monooleate which subsequently transformed into gel. The gel microstructure was analyzed by PPL microscopy and SAXS. Lactose particles recovered from gels after 48 h were analyzed for polymorphism using techniques such as FTIR, XRD, DSC and TGA. Particle size, morphology and aerosolisation properties of prepared lactose were analyzed using Anderson cascade impactor. In situ seeding followed by growth of lactose crystals took place in gels with cubic microstructure as revealed by PPL microscopy and SAXS. Elongated (size 71 lm) lactose particles with smooth surface containing mixture of a and b-lactose was recovered from gel, however percentage of a-lactose was more as compared to b-lactose. The aerosolisation parameters such as RD, ED, %FPF and % recovery of lactose recovered from gel (LPL) were found to be comparable to RespitoseÒ ML001. Thus LC phase (cubic) can be used for engineering of lactose crystals so as to obtain particles with smooth surface, high elongation ratio and further they can be used as carrier in DPI formulations. Ó 2014 Elsevier B.V. All rights reserved.
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1. Introduction
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Nowadays, particle engineering techniques have gained prime importance owing to their role in drug delivery process. Drug delivery processes are comprised of administration of drug, its release and transport to the site of action (Jain, 2008). Pulmonary drug delivery is one of the areas wherein particle engineering plays a vital role. Formulation scientists are continuously working in the area of particle engineering so as improve traditional techniques such as milling and advanced techniques including spray drying, spray freeze drying and supercritical fluid technology. Some of these techniques are harsh whereas some are quite promising (Shoyele and Cawthorne, 2006). Thus searching newer methods for particle engineering is one of the thrust areas of formulation scientists. Lyotropic liquid crystalline (LC) phases as a drug delivery system have attracted most of the researchers owing to their unique properties including their structural resemblance to human membranes, large surface area and high solubilization capacities (Patil
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⇑ Corresponding author at: Department of Pharmaceutics, Bharati Vidyapeeth University, Poona College of Pharmacy, Erandwane, Maharashtra, India. Tel.: +91 20 25437237; fax: +91 20 25439383. E-mail address: [email protected] (S.S. Patil).
et al., 2013). Besides drug delivery, LC phases have been used for crystallization of membrane proteins (Caffrey, 2003). Glycerol monooleate (GMO), a polar lipid is one of the metabolites of triglycerides (Patton, 1979). It has been reported to form variety of LC phases including reverse isotropic micellar solution (L2), lamellar (La), inverted type (reverse) hexagonal (HII), and cubic (V2) having different physical properties and hence being explored as a drug delivery systems including biomolecules (Chernik, 2000; Larsson, 1983; Qiu and Caffrey, 2000). However, to the best of our knowledge utility of LC phases as one of the particle engineering techniques has not yet been assessed. Dry powder inhaler (DPI) is one of the drug delivery systems used to deliver the drug by pulmonary route. DPIs present advantages such as propellant-free, portable and easy to operate. Further these are low-cost devices and improve stability of the formulation due to dry state (Carpenter et al., 1997; Prime et al., 1997). The majority of DPI formulations consist of a powder mixture of coarse carrier particles and micronized drug particles having aerodynamic particle diameters in the range of 1–5 lm (Iida et al., 2003). The improvement in dose accuracy and minimization of dose variability is achieved by the use of carrier particles which when mixed with drug improve its flowability (Schiavone et al., 2004). According to the literature, carrier particles having size in the range of 63–90 lm, smooth surface and high elongation ratios are desirable
http://dx.doi.org/10.1016/j.ejps.2014.11.007 0928-0987/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Patil, S.S., et al. Liquid crystalline phase as a probe for crystal engineering of lactose: Carrier for pulmonary drug delivery. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.11.007
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for delivering the drug to the site of action (Zeng et al., 1999, 2000). Particulate interactions within drug and carrier play vital role with respect to the drug delivery by DPIs. The physical forces of interactions such as van der Waals forces, electrostatic charges, capillary forces and mechanical interlocking dominate the interparticulate interactions (both cohesion and adhesion). Further particle size, shape, surface roughness, the intensity and duration of drugcarrier mixing, contamination of carrier particles and relative humidity (RH) govern magnitude of these forces (Telko and Hickey, 2005; de Boer et al., 2003). For example, the improvement in surface smoothness of lactose carrier particles improved respirable fraction of salbutamol sulfate from the RotahalerÒ (Ganderton, 1992) which was attributed to the reduction in adhesion forces between the drug and carrier particles upon smoothing carrier surface. The literature states that generally the respirable drug fraction increases with the use of carrier particles having small size (Kaialy et al., 2012a; Young et al., 2011; Le et al., 2012). Higher amounts of fines in the carrier particles (Islam et al., 2004; Kaialy et al., 2011) or more surface roughness of the same (Kaialy et al., 2012b) have shown higher amounts of drug deposition on lower airway regions. Carrier particles with more elongated shape and rough surface have shown reduction in drug–carrier adhesion (Kaialy et al., 2012c; Podczeck et al., 1996). Further better drug content homogeneity within DPI formulations was observed for carriers having rough surface (Kaialy et al., 2012c, 2012b; Flament et al., 2004). The flowability of carrier particles has shown to affect the performance of DPI formulations. The amount of drug loss or deposition of drug on the throat has been observed with carrier particles with poor flowability (Kaialy et al., 2012b). Additionally, high drug loss and low drug emission upon aerosolisation was observed in case of carrier particles with high bulk and tap densities. (Kaialy et al., 2012c). Reports on effect of particle size of the carrier on drug deposition are also well documented (French et al., 1996; Steckel and Muller, 1997). Lactose is most commonly used carrier particles in the formulation of DPI owing to its well investigated toxicity profile, physical and chemical stability along with its compatibility with drug and most importantly its broad availability at low price (Pilcer and Amighi, 2010). Lactose, 4-(b-D-galactosido-)-D-glucose can exist as a single hydrated form, a-lactose monohydrate (LaH2O) and three dehydrated forms, b-lactose (Lb), stable anhydrous a-lactose (LaS) and unstable hygroscopic anhydrous a-lactose (LaH) (Kirk et al., 2007). The crystal habit of lactose is greatly influenced by the recrystallization conditions. It is reported that recrystallization of lactose above 93.5 °C yields b-lactose while below this temperature a-lactose monohydrate (a-LM) is obtained. Out of the above mentioned forms of lactose, a-LM is most widely used as pharmaceutical excipient (Kibbe, 2000). Different methods have been employed for carrying out crystallization of lactose which includes seeding technique (Liang et al., 1991), precipitation of lactose using anti-solvent such as ethanol (Bund and Pandit, 2007), acetone (Larhrib et al., 2003), methanol (Leviton, 1949), DMSO (Dincer et al., 1999), ultrasound assisted antisolvent crystallization (Dhumal et al., 2008; Bund and Pandit, 2007a) and carbopol gel (Zeng et al., 2001). Besides simple milling (Inhalation grades available with DFE Pharma, Germany) crystallization techniques involving use of antisolvent, ultrasound and carbopol gels have presented lactose which can be used as a carrier in DPI. Further engineering of lactose particles in order to improve dispersibility so as obtain higher FPF and lower ED has been reported in literature which includes mechanofusion of lactose with magnesium or sucrose stearate (Kumon et al., 2006, 2008), wet-smoothing using solvent and magnesium stearate (Ferrari et al., 2004; Young et al., 2002), surface erosion using high-speed elliptical-rotor-type mixer (Iida et al., 2004), surface dissolution using aqueous-ethanol solution or by means of temperature
(El-Sabawi et al., 2006; Iida et al., 2006), coating of lactose particles with magnesium stearate or HPMC (Iida et al., 2005). It was observed that elongated lactose crystals with smooth surface could be produced using anti-solvent ethanol. However at the same time increased number of primary nuclei lead to generation of small crystals. Ultrasound has been reported to produce lactose crystals with desired quality; however erosion of ultrasonic probe may contaminate the product (Hansson, 1980). Lactose crystallized from carbopol gel resulted in large regular crystals with smooth surface and improved fine particle fraction (FPF). In the present work, suitability of LC phase for engineering lactose particles was assessed. Gel consisting of cubic phase is used for crystallization of a-LM. The gel microstructure was analyzed by plane polarized (PPL) microscopy and small angle X ray scattering (SAXS). The lactose particles harvested from gel were characterized by Fourier Transform Infra Red spectroscopy, X-ray diffraction analysis, Differential scanning Calorimetry, Thermogravimetric analysis and Scanning Electron Microscopy. The aerosolisation properties of the particles were determined by using salbutamol sulfate as a model drug and compared to marketed lactose particles (RespitoseÒ ML001) used for DPI formulation.
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2. Materials and methods
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2.1. Materials
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Glyceryl monooleate (GMO, Rylo MG 19 Pharma), Salbutamol sulfate (SS) was a gift sample from Danisco culture, Denmark and Cipla Ltd. Mumbai, India respectively. Lactose monohydrate (RespitoseÒ ML001) was purchased from DFE Pharma, Germany.
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2.2. Method
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Glyceryl monooleate (GMO) was used for the preparation of gel. To describe in brief, saturated solution of lactose (20%w/v) in deionised water was prepared. GMO was melted. The molten GMO was diluted with lactose solution at 70 °C so as to obtain 35%v/v aqueous mixture of GMO. The dispersion transformed into translucent gel upon cooling. The gel became turbid when kept undisturbed for two days (48 h) indicating crystallization of lactose (LPL). The crystals so formed were recovered by addition of isopropyl alcohol which acts as a solvent for GMO and antisolvent for lactose. The suspension was filtered to obtain lactose crystals which were washed with 60% (v/v) ethanol followed by 100% (v/ v) ethanol. The crystals were allowed to dry overnight before drying in vacuum oven at 70 °C for 3 h. In order to assess reproducibility, the method was repeated twice and the lactose collected was analyzed further.
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2.3. Characterization
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2.3.1. Plane polarized light microscopy Polarized light microscopy was used to confirm the type of mesophase formed by GMO in the gel form after addition of lactose (Rosevear, 1954). Hydrated gel was transferred to a specially fabricated glass tube (internal diameter 0.5 cm) and examined for presence or absence of birefringence under a microscope at 25 ± 0.5 °C with a k/4 plate oriented at 45° to the polarizer axes under 40 magnification (Nikon Eclipse E 600, Nikon Instech Co., Japan).
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2.3.2. Small angle X-ray scattering (SAXS) In order to confirm the type of mesophase formed during crystallization of lactose, SAXS experiments were performed on a Bruker Nanostar with rotating Cu anode and pinhole geometry using a copper Ka radiation of wavelength 1.54 Å. The current
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requirement of anode was 100 mA and a potential difference of 45 kV. Lactose containing gel was taken in a quartz capillary of 2 mm diameter and 10 lm wall thickness. In order to obtain correct results background from an empty capillary was subtracted, after accounting for the sample absorption. Temperature was controlled using Bruker Peltier heating cooling unit. HISTAR gas-filled multiwire detector was used for collection of data. Scattering from the sample was measured until the scattered intensity gave at least 3 million counts on the detector. 2.3.3. Fourier transform infra-red spectroscopy (FTIR) IR spectrum for LPL and LM (RespitoseÒ ML001) were recorded using Jasco FTIR-4100 Fourier Transform Infrared Spectrophotometer (Jasco Corporation, Japan). The samples were mixed with dry potassium bromide and a total of 300 scans were collected from 4000 to 400 cm1. Jasco Spectra Manager Version 2 was used for data acquisition and analysis. 2.3.4. Thermogravimetric analysis (TGA) LPL and LM sample (30–40 mg) was placed in platinum crucibles separately and heated over a temperature range of 25–700 °C at a constant rate of 10 °C/min. Nitrogen gas was purged at flow rate of 50 ml/min in order to maintain inert atmosphere during analysis. Loss of sample mass as a function of temperature was recorded using TA-60WS Thermogravimetric analyzer (Shimandzu, Japan). 2.3.5. Differential scanning calorimetry (DSC) Calorimetric measurements were performed with Mettler Toledo 821e instrument equipped with an intracooler (Mettler Toledo, Switzerland), and calibrated with indium and zinc standards. A 10 ± 3 mg of LPL and LM sample was placed in closed aluminum crucibles separately. The crucibles were sealed and subjected to heating from 0 to 250 °C at the scanning rate of 10 °C/min. 2.3.6. X-ray powder diffraction (XRPD) X-ray diffractometer (D8 Advance, Bruker AXS Inc. Madison, USA) was used for recording XRPD patterns of LPL and LM samples. The samples were irradiated with monochromatized Cu Ka radiation (1.542 A°) and analyzed in 2h range of 2–25°.
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2.3.7. Particle size distribution Particle size was measured by Malvern Mastersizer 2000 (Malvern, UK) working on the principle of laser diffraction. Ethanol was used as dispersant for each measurement. Malvern software version 5.2 was used for data acquisition. Analysis was done in triplicate.
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2.3.8. Powder flow
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prepared LPL samples were coated with thin gold–palladium layer using Auto fine coater (Joel, JFC, Tokyo, Japan) after mounting on aluminum stud. Samples were then analyzed with scanning electron microscope (Jeol, JSM-6360, Tokyo, Japan) operated at 10 kv acceleration voltage. The images obtained were processed by Image J software in order to determine various shape descriptors such as elongation ratio (E = length/width) and Circularity (C), defined as the degree to which the particle is similar to a circle.
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2.3.10. In-vitro deposition study in cascade impactor Micronized SS (3.2 ± 1.1 lm) was mixed with LPL (63–90 lm fraction) in the ratio of 1:67.5 (w:w) as reported in previous literature (Kaialy and Nokhodchi, 2012d). The sequential mixing process was performed in stoppered vials placed on a cyclone mixer for 5 s till the desired ratio was obtained. The mixture was then finally blended in double cone blender for 30 min at 40 rpm. Content uniformity (SS content) of the blend was determined using UV spectrophotometry (V-530, UV/VIS spectrophotometer, JASCO International Co., Ltd. Japan) at fixed wavelength of 276 nm. Hard gelatin capsules were filled with the prepared blend manually so as to contain 492 ± 10 lg of SS in each capsule. Eight stage, nonviable Anderson cascade impactor along with a preseparator (Westech Private Instruments; model no. WP-ACISS-0289), operating at flow rate of 28.3 L/min was used to analyze dispersion behavior of the prepared powder blend. The powder samples present within capsules were aerosolized using RotahalerÒ. UV spectrophotometry method was used to analyze SS deposited at different locations of the impactor. Various aerosolisation parameters were determined. The recovered dose (RD), sum of SS collected from capsule, inhaler device, pre-separator, induction port and all stages of impactor, emitted dose (ED) i.e. amount of SS released from inhaler device which is sum of amount of SS collected at pre-separator, induction port and all stages of impactor were determined. The capacity of the formulation to be fluidised and deagglomerated in time so as to release the drug from carrier particle in order to get deposited in the appropriate level of the impinger can be measured using fine particle dose (FPD) and fine particle fraction (FPF). FPD represents the mass of drug particles that have a aerodynamic diameter 1, higher the value of E more elongated the particle and circularity indicates how closely the projected area of a particle approached a circle (Dhumal et al., 2008; Watling et al., 2010). Elongated ratio of LPL was 1.56 ± 0.06 with a circularity of about 0.69 which indicates presence of elongated and non-circular particles in LPL. Moreover, Ò the values were comparable to Respitose ML001 (P > 0.05). The reason for high E for LPL may be attributed to the crystal growth rate. The swelling of GMO might have seeded some rod-shaped lactose crystals which acted as nuclei for other lactose molecules.
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Table 2 TGA data indicating weight loss of RespitoseÒ ML001 and LPL. Sr. no.
Sample
Onset temp. (°C)
End temp. (°C)
Weight loss (%)
1
a-LM
131.93 222.89 284.33
143.1 246.46 315.13
4.602 15.72 54.45
109.53 228.28 278.93
137.10 242.54 309.88
2.519 13.22 55.43
2
LPL
Thus some crystal faces of these nuclei might have grown faster when compared to the other faces. The viscous nature of cubic phase might have played vital role in crystallization of elongated lactose particles. In order to support our hypothesis we did scanning electron microscopy of LPL and lactose seeds separated from gel after 5 h. Images for the same are depicted in Fig. 6.
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3.8. Powder flow
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Static (CI) and dynamic methods (angle of repose) were used to determine flow properties of LPL and RespitoseÒ ML001. The values of CI and angle of repose prove an estimate of powder flow. Lower the values better is the powder flow. As revealed from Table 3, the values of CI and angle of repose for LPL and RespitoseÒ ML001 were comparable (P > 0.05). The powder flow for LPL was in the acceptable limits and thus suggested its suitability for use as a carrier in DPI.
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3.9. Scanning electron microscopy
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The SEM photomicrographs of lactose seeds showed rod shaped crystals whereas LPL showed elongated lactose crystals with a size in the range of 63–90 lm supporting particle size analysis data (Fig. 6). It is proven that the elongated particles are expected to travel a longer distance before impaction occurs in comparison to less elongated particles of similar mass as a result of lower relative aerodynamic diameters of the former. Moreover, the surface of LPL was smooth. The stagnant conditions rather than random fluctuations are known to have a control on crystallization. The viscous cubic phase might have provided a turbulence free homogeneous environment wherein the lactose crystals would have grown to maturity without any surface defects. Yet another reason for obtaining lactose particles with smooth surface could be attributed to the harvesting process. In the present work, the lactose crystals were initially washed with aqueous ethanol (60%v/v) followed by absolute ethanol (100%). After separation from gel traces of mother liquor might exist on the surface of lactose crystals. Thus washing with absolute ethanol will spontaneously crystallize needle shaped fine lactose crystals on surface of lactose particles. Prewashing with dilute alcohol removed most of the mother liquor from crystal surface making it smooth. However use of more dilute ethanol can lead to erosion of lactose surface. The surface smoothing effect of aqueous ethanol has been reported earlier (Zeng et al., 2001).
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3.10. In-vitro aerosol deposition studies
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The aerosolisation properties of LPL were compared with commercial RespitoseÒ ML001 powder. Salbutamol sulfate was used as model drug for the deposition study. Micronized SS was mixed with 63–90 sieved fractions of LPL in a ratio of 1:67.5 and filled in hard gelatin capsule. The content uniformity was found to be in the range of 96.47–101.35% for the prepared batches. The percent SS recovery for both the samples was in the range of 90.85 ± 1.72–94.03 ± 1.52 (Table 4) which is within the acceptable limits (75–125%) for mass balance (Bryon et al., 1994). Formulations containing SS blended with RespitoseÒ ML001 showed RD; 462.66 ± 21.6 lg, ED; 376.97 ± 7.95 lg and %FPF;
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Table 3 Particle size, elongation ratio, circularity, CI and angle of repose of RespitoseÒ ML001 and LPL. Type of lactose Ò
Respitose ML001 LPL
Particle size (lm)
Elongation ratio#
Circularity#
CI⁄
Angle of repose⁄
68.23 ± 5.754 71.66 ± 6.274
1.60 ± 0.04 1.56 ± 0.06
0.64 ± 0.05 0.69 ± 0.04
23 ± 2 25 ± 1
38 ± 2 40 ± 1
mean ± SD, n = 50# and n = 6⁄, P > 0.05 for unpaired t-test.
Please cite this article in press as: Patil, S.S., et al. Liquid crystalline phase as a probe for crystal engineering of lactose: Carrier for pulmonary drug delivery. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.11.007
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Fig. 6. SEM photomicrographs of lactose at different stages. (A) Lactose seed crystals after 5 h. (B) Fully grown lactose crystals (LPL) at 200X. (C) LPL at 2000X and (D) RespitoseÒ ML001.
Table 4 Different aerosolisation parameters obtained from deposition of salbutamol sulfate in Anderson cascade impactor. Sr. no.
Parameter
LPL
RespitoseÒ ML001
1 2 3 4
RD (lg) % Recovery⁄ ED (lg) %FPF
447 ± 27.16 90.85 ± 1.72 363.37 ± 9.99 47.44 ± 1.62
462.66 ± 21.6 94.03 ± 1.52 376.97 ± 7.95 49.36 ± 1.17
n = 3, ⁄Mean ± RSD, SD (P > 0.05) for unpaired t-test.
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49.36 ± 1.17% whereas those with LPL showed RD; 447 ± 27.16 lg, ED; 363.37 ± 9.99 lg and %FPF; 47.44 ± 1.62%. As it can be seen that all the aerosolization parameters are high (even though statistically insignificant, P > 0.05) for formulation containing RespitoseÒ ML001 when compared to LPL, such difference in aerosolisation parameters could be attributed to the fact that commercial RespitoseÒ ML001 might be containing fines generated during manufacturing. The fines might have reduced the adhesive forces between carrier surface and drug by adhering to the surface crevices and asperities of lactose carrier leading to improvement in de-agglomeration behavior of the drug (Zeng et al., 1998). The morphological features such as size, shape and surface smoothness have an impact on deposition profiles. The elongated particles exhibit small aerodynamic diameters when compared to spherical particles with identical mass or volume (Hickey, 1992). More elongated particles are expected to travel long distance before impaction and adhere more drug particles when compared to spherical particles. Additionally they are expected to experience drag forces of the air stream for longer period of time resulting in higher proportion of drug being detached from them leading to higher values of FPF. In the current work aerosolisation properties for LPL and RespitoseÒ ML001 were found to be comparable (P > 0.05). Thus it can be concluded that liquid crystalline phase (cubic) can be used for engineering of a–LM crystals in order to obtain particles with high elongation ratio, smooth surface and improved flow.
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4. Conclusion
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In the present work, suitability of liquid crystalline phase for engineering lactose particles was analyzed. Gels with cubic phase were obtained wherein in situ seeding followed by growth of lactose crystals took place. PPL microscopy and SAXS studies revealed existence of cubic mesophase within gel. Elongated lactose crystals with smooth surface were obtained as confirmed from particle size analysis, FTIR, DSC, XRD, SEM and TGA studies. The particle size and aerosolisation data for prepared lactose crystals explored their utility as a carrier in DPI. Thus it can be concluded that cubic phase
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can be used as a probe for crystal engineering of lactose particles. Further the prepared particles can be used as a carrier in dry powder inhalation formulations.
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Acknowledgements
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Dr. Sharvil Patil thank Mr. Prashant Pisal, Poona College of Pharmacy, Pune, India and Mr. Sudhir Pagire, University of Bradford, UK for assistance in thermogravimetric analysis and scanning Electron Microscopy respectively.
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Iida, K., Hayakawa, Y., Okamoto, H., Danjo, K., Leuenberger, H., 2003a. Preparation of dry powder inhalation by surface treatment of lactose carrier particles. Chem. Pharm. Bull. 51, 1–5. Iida, K., Hayakawa, Y., Okamoto, H., Danjo, K., Luenberger, H., 2003b. Effect of surface covering of lactose carrier particles on dry powder inhalation properties of salbutamol sulfate. Chem. Pharm. Bull. 51 (12), 1455–1457. Iida, K., Inagaki, Y., Todo, H., Okamoto, H., Danjo, K., Luenberger, H., 2004. Effects of surface processing of lactose carrier particles on dry powder inhalation properties of salbutamol sulfate. Chem. Pharm. Bull. 52, 938–942. Iida, K., Todo, H., Okamoto, H., Danjo, K., Leuenberger, H., 2005. Preparation of dry powder inhalation with lactose carrier particles surface-coated using a Wurster fluidized bed. Chem. Pharm. Bull. 53, 431–434. Islam, N., Stewart, P., Larson, I., Hartley, P., 2004. Lactose surface modification by decantation: are drug-fine lactose ratios the key to better dispersion of salmeterol xinafoate from lactose-interactive mixtures? Pharm. Res. 21, 492–499. Kaialy, W., Alhalaweh, A., Velaga, S.P., Nokhodchi, A., 2012a. Influence of lactose carrier particle size on the aerosol performance of budesonide from a dry powder inhaler. Powder Technol. 227, 74–85. Kaialy, W., Martin, G.P., Larhrib, H., Ticehurst, M.D., Kolosionek, E., Nokhodchi, A., 2012b. The influence of physical properties and morphology of crystallised lactose on delivery of salbutamol sulphate from dry powder inhalers. Colloids Surf. B 89, 29–39. Kaialy, W., Martin, G.P., Ticehurst, M.D., Royall, P., Mohammad, M.A., Murphy, J., Nokhodchi, A., 2011. Characterisation and deposition studies of recrystallised lactose from binary mixtures of ethanol/butanol for improved drug delivery from dry powder inhalers. AAPS J. 13, 30–43. Kaialy, W., Nokhodchi, A., 2012. Antisolvent crystallisation is a potential technique to prepare engineered lactose with promising aerosolisation properties: effect of saturation degree. Int. J. Pharm. 437, 57–69. Kaialy, W., Ticehurst, M.D., Nokhodchi, A., 2012c. Dry powder inhalers: mechanistic evaluation of lactose formulations containing salbutamol sulphate. Int. J. Pharm. 423, 184–194. Khankari, R., Law, D., Grant, D., 1992. Determination of water content in pharmaceutical hydrates by differential scanning calorimetry. Int. J. Pharm. 89, 117–127. Kibbe, A., 2000. Lactose. In: Handbook of Pharmaceutical Excipients, third ed. London Pharmaceutical Press, London, pp. 276–285. Kirk, J.H., Dann, S.E., Blatchford, C.G., 2007. Lactose: a definitive guide to polymorph determination Int. J. Pharm. 334, 103–114. Kumon, M., Machida, S., Suzuki, M., Kusai, A., Yonemochi, E., Terada, K., 2008. Application and mechanism of inhalation profile improvement of DPI formulations by mechanofusion with magnesium stearate. Chem. Pharm. Bull. 56, 617–625. Kumon, M., Suzuki, M., Kusai, A., Yonemochi, E., Terada, K., 2006. Novel approach to DPI carrier lactose with mechanofusion process with additives and evaluation by IGC. Chem. Pharm. Bull. 54, 1508–1514. Larhrib, H., Martin, G., Prime, D., Marriot, C., 2003. Characterization and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolized salbutamol sulphate from dry powder inhalers. Eur. J. Pharm. Sci. 19, 211–221. Larsson, K., 1983. Two cubic phases in monoolein/water system. Nature 304, 664. Le, V.N.P., Thi, T.H.H., Robins, E., Flament, M., 2012. Dry powder inhalers: study of the parameters influencing adhesion and dispersion of fluticasone propionate. AAPS PharmSciTech 13, 477–484. Leviton, A., 1949. Methanol extraction of lactose and soluble proteins from skim milk powder. Ind. Eng. Chem. 41, 1351–1357.
Liang, B., Shi, Y., Hartel, R., 1991. Growth rate dispersion effects on lactose crystal size distributions from a continuous cooling crystallizer. J. Food Sci. 56, 848– 854. Patil, S., Venugopal, E., Bhat, S., Mahadik, K., Paradkar, A., 2013. Mapping Ion induced mesophasic transformation in lyotropic in situ gelling system and its correlation with pharmaceutical performance. Pharm. Res. 30, 1906–1914. Patton, J., Carey, M., 1979. Watching fat digestion. Science 204, 145–148. Pilcer, G., Amighi, K., 2010. Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm. 392, 1–19. Pilcer, G., Wauthoz, N., Amighi, K., 2012. Lactose characteristics and the generation of the aerosol. Adv. Drug Deliv. Rev. 64, 233–256. Podczeck, F., Newton, J.M., James, M.B., 1996. The adhesion force of micronized salmeterol xinafoate particles to pharmaceutically relevant surface materials. J. Phys. D 29, 1878. Prime, D., Atkins, P., Slater, A., Sumby, B., 1997. Review of dry powder inhalers. Adv. Drug Deliv. Rev. 26 (1), 51–58. Qiu, H., Caffrey, M., 2000. The phase diagram of the monoolein/water system: metastability and equilibrium aspects. Biomaterials 21, 223–234. Rosevear, F., 1954. The microscopy of the liquid crystalline neat and middle phases of soaps and synthetic detergents. J. Am. Oil Chem. Soc. 31, 628–639. Schiavone, H., Palakodaty, S., Clark, A., York, P., Tzannis, S., 2004. Evaluation of SCFengineered particle based lactose blends in passive dry powder inhalers. Int. J. Pharm. 281 (1), 55–66. Shah, J., Sadhale, Y., Chulukuri, D., 2001. Cubic phase gels as drug deliverysystems. Adv. Drug Deliv. Rev. 47 (2–3), 229–250. Shoyele, S.A., Cawthorne, S., 2006. Particle engineering techniques for inhaled biopharmaceuticals. Adv. Drug Deliv. Rev. 58 (9–10), 1009–1029. Stark, J., Wallace, H., 1976. In: Chemistry Data Book, SI ed. John Murry, London, pp. 122. Steckel, H., Muller, B.W., 1997. In vitro evaluation of dry powder inhalers II: influence of carrier particle size and concentration on in vitro deposition. Int. J. Pharm. 154, 31–37. Telko, M., Hickey, A., 2005. Dry powder inhaler formulation. Respir. Care 50, 1209– 1227. Watling, C., Elliott, J., Cameron, R., 2010. Entrainment of lactose inhalation powders: a study using laser diffraction. Eur. J. Pharm. Sci. 40, 352–358. Yaghmur, A., Laggner, P., Zhang, S., Rappolt, M., 2007. Tuning curvature and stability of monoolein bilayers by designer lipid-like peptide surfactants. PLoS ONE 2 (5), e479. Young, P., Cocconi, D., Colombo, P., Bettini, R., Price, R., Steele, D., Tobyn, M., 2002. Characterization of a surface modified dry powder inhalation carrier prepared by ‘‘particle smoothing’’. J. Pharm. Pharmacol. 54, 1339–1344. Young, P.M., Owen, W., Jesslynn, O., Traini, D., 2011. The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers. Int. J. Pharm. 416, 129–135. Zeng, X., Martin, G., Marriot, C., Pritchard, J., 2001. Crystallization of lactose from carbopol gels. Pharm. Res. 17 (7), 879–886. Zeng, X., Martin, G., Marriott, C., Pritchrd, J., 2000. The Influence of crystallization conditions on the morphology of lactose intended for use as a carrier for dry powder aerosols. J. Pharm. Pharmacol. 52, 633–643. Zeng, X., Martin, G., Tee, S., Ghoush, A., Marriott, C., 1999. Effects of particle size and adding sequence of fine lactose on the deposition of salbutamol sulphate from a dry powder formulation. Int. J. Pharm. 182, 133–144. Zeng, X., Martin, G., Tee, S., Marriot, C., 1998. The role of fine lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro. Int. J. Pharm. 176, 99–110.
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Please cite this article in press as: Patil, S.S., et al. Liquid crystalline phase as a probe for crystal engineering of lactose: Carrier for pulmonary drug delivery. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.11.007
No. of Pages 8, Model 5G
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Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps 5 6
Liquid crystalline phase as a probe for crystal engineering of lactose: Carrier for pulmonary drug delivery
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Q1
Sharvil S. Patil a,⇑, Kakasaheb R. Mahadik a, Anant R. Paradkar b a b
Bharati Vidyapeeth University, Poona College of Pharmacy, Department of Pharmaceutics, Erandwane, Pune 411038, India Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford BD7 1DP, UK
a r t i c l e
i n f o
Article history: Received 1 August 2014 Received in revised form 14 November 2014 Accepted 14 November 2014 Available online xxxx Keywords: Cubic phase Lactose monohydrate Cascade impactor Salbutamol sulfate Glyceryl monooleate
a b s t r a c t The current work was undertaken to assess suitability of liquid crystalline phase for engineering of lactose crystals and their utility as a carrier in dry powder inhalation formulations. Saturated lactose solution was poured in molten glyceryl monooleate which subsequently transformed into gel. The gel microstructure was analyzed by PPL microscopy and SAXS. Lactose particles recovered from gels after 48 h were analyzed for polymorphism using techniques such as FTIR, XRD, DSC and TGA. Particle size, morphology and aerosolisation properties of prepared lactose were analyzed using Anderson cascade impactor. In situ seeding followed by growth of lactose crystals took place in gels with cubic microstructure as revealed by PPL microscopy and SAXS. Elongated (size 71 lm) lactose particles with smooth surface containing mixture of a and b-lactose was recovered from gel, however percentage of a-lactose was more as compared to b-lactose. The aerosolisation parameters such as RD, ED, %FPF and % recovery of lactose recovered from gel (LPL) were found to be comparable to RespitoseÒ ML001. Thus LC phase (cubic) can be used for engineering of lactose crystals so as to obtain particles with smooth surface, high elongation ratio and further they can be used as carrier in DPI formulations. Ó 2014 Elsevier B.V. All rights reserved.
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1. Introduction
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Nowadays, particle engineering techniques have gained prime importance owing to their role in drug delivery process. Drug delivery processes are comprised of administration of drug, its release and transport to the site of action (Jain, 2008). Pulmonary drug delivery is one of the areas wherein particle engineering plays a vital role. Formulation scientists are continuously working in the area of particle engineering so as improve traditional techniques such as milling and advanced techniques including spray drying, spray freeze drying and supercritical fluid technology. Some of these techniques are harsh whereas some are quite promising (Shoyele and Cawthorne, 2006). Thus searching newer methods for particle engineering is one of the thrust areas of formulation scientists. Lyotropic liquid crystalline (LC) phases as a drug delivery system have attracted most of the researchers owing to their unique properties including their structural resemblance to human membranes, large surface area and high solubilization capacities (Patil
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⇑ Corresponding author at: Department of Pharmaceutics, Bharati Vidyapeeth University, Poona College of Pharmacy, Erandwane, Maharashtra, India. Tel.: +91 20 25437237; fax: +91 20 25439383. E-mail address: [email protected] (S.S. Patil).
et al., 2013). Besides drug delivery, LC phases have been used for crystallization of membrane proteins (Caffrey, 2003). Glycerol monooleate (GMO), a polar lipid is one of the metabolites of triglycerides (Patton, 1979). It has been reported to form variety of LC phases including reverse isotropic micellar solution (L2), lamellar (La), inverted type (reverse) hexagonal (HII), and cubic (V2) having different physical properties and hence being explored as a drug delivery systems including biomolecules (Chernik, 2000; Larsson, 1983; Qiu and Caffrey, 2000). However, to the best of our knowledge utility of LC phases as one of the particle engineering techniques has not yet been assessed. Dry powder inhaler (DPI) is one of the drug delivery systems used to deliver the drug by pulmonary route. DPIs present advantages such as propellant-free, portable and easy to operate. Further these are low-cost devices and improve stability of the formulation due to dry state (Carpenter et al., 1997; Prime et al., 1997). The majority of DPI formulations consist of a powder mixture of coarse carrier particles and micronized drug particles having aerodynamic particle diameters in the range of 1–5 lm (Iida et al., 2003). The improvement in dose accuracy and minimization of dose variability is achieved by the use of carrier particles which when mixed with drug improve its flowability (Schiavone et al., 2004). According to the literature, carrier particles having size in the range of 63–90 lm, smooth surface and high elongation ratios are desirable
http://dx.doi.org/10.1016/j.ejps.2014.11.007 0928-0987/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Patil, S.S., et al. Liquid crystalline phase as a probe for crystal engineering of lactose: Carrier for pulmonary drug delivery. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.11.007
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for delivering the drug to the site of action (Zeng et al., 1999, 2000). Particulate interactions within drug and carrier play vital role with respect to the drug delivery by DPIs. The physical forces of interactions such as van der Waals forces, electrostatic charges, capillary forces and mechanical interlocking dominate the interparticulate interactions (both cohesion and adhesion). Further particle size, shape, surface roughness, the intensity and duration of drugcarrier mixing, contamination of carrier particles and relative humidity (RH) govern magnitude of these forces (Telko and Hickey, 2005; de Boer et al., 2003). For example, the improvement in surface smoothness of lactose carrier particles improved respirable fraction of salbutamol sulfate from the RotahalerÒ (Ganderton, 1992) which was attributed to the reduction in adhesion forces between the drug and carrier particles upon smoothing carrier surface. The literature states that generally the respirable drug fraction increases with the use of carrier particles having small size (Kaialy et al., 2012a; Young et al., 2011; Le et al., 2012). Higher amounts of fines in the carrier particles (Islam et al., 2004; Kaialy et al., 2011) or more surface roughness of the same (Kaialy et al., 2012b) have shown higher amounts of drug deposition on lower airway regions. Carrier particles with more elongated shape and rough surface have shown reduction in drug–carrier adhesion (Kaialy et al., 2012c; Podczeck et al., 1996). Further better drug content homogeneity within DPI formulations was observed for carriers having rough surface (Kaialy et al., 2012c, 2012b; Flament et al., 2004). The flowability of carrier particles has shown to affect the performance of DPI formulations. The amount of drug loss or deposition of drug on the throat has been observed with carrier particles with poor flowability (Kaialy et al., 2012b). Additionally, high drug loss and low drug emission upon aerosolisation was observed in case of carrier particles with high bulk and tap densities. (Kaialy et al., 2012c). Reports on effect of particle size of the carrier on drug deposition are also well documented (French et al., 1996; Steckel and Muller, 1997). Lactose is most commonly used carrier particles in the formulation of DPI owing to its well investigated toxicity profile, physical and chemical stability along with its compatibility with drug and most importantly its broad availability at low price (Pilcer and Amighi, 2010). Lactose, 4-(b-D-galactosido-)-D-glucose can exist as a single hydrated form, a-lactose monohydrate (LaH2O) and three dehydrated forms, b-lactose (Lb), stable anhydrous a-lactose (LaS) and unstable hygroscopic anhydrous a-lactose (LaH) (Kirk et al., 2007). The crystal habit of lactose is greatly influenced by the recrystallization conditions. It is reported that recrystallization of lactose above 93.5 °C yields b-lactose while below this temperature a-lactose monohydrate (a-LM) is obtained. Out of the above mentioned forms of lactose, a-LM is most widely used as pharmaceutical excipient (Kibbe, 2000). Different methods have been employed for carrying out crystallization of lactose which includes seeding technique (Liang et al., 1991), precipitation of lactose using anti-solvent such as ethanol (Bund and Pandit, 2007), acetone (Larhrib et al., 2003), methanol (Leviton, 1949), DMSO (Dincer et al., 1999), ultrasound assisted antisolvent crystallization (Dhumal et al., 2008; Bund and Pandit, 2007a) and carbopol gel (Zeng et al., 2001). Besides simple milling (Inhalation grades available with DFE Pharma, Germany) crystallization techniques involving use of antisolvent, ultrasound and carbopol gels have presented lactose which can be used as a carrier in DPI. Further engineering of lactose particles in order to improve dispersibility so as obtain higher FPF and lower ED has been reported in literature which includes mechanofusion of lactose with magnesium or sucrose stearate (Kumon et al., 2006, 2008), wet-smoothing using solvent and magnesium stearate (Ferrari et al., 2004; Young et al., 2002), surface erosion using high-speed elliptical-rotor-type mixer (Iida et al., 2004), surface dissolution using aqueous-ethanol solution or by means of temperature
(El-Sabawi et al., 2006; Iida et al., 2006), coating of lactose particles with magnesium stearate or HPMC (Iida et al., 2005). It was observed that elongated lactose crystals with smooth surface could be produced using anti-solvent ethanol. However at the same time increased number of primary nuclei lead to generation of small crystals. Ultrasound has been reported to produce lactose crystals with desired quality; however erosion of ultrasonic probe may contaminate the product (Hansson, 1980). Lactose crystallized from carbopol gel resulted in large regular crystals with smooth surface and improved fine particle fraction (FPF). In the present work, suitability of LC phase for engineering lactose particles was assessed. Gel consisting of cubic phase is used for crystallization of a-LM. The gel microstructure was analyzed by plane polarized (PPL) microscopy and small angle X ray scattering (SAXS). The lactose particles harvested from gel were characterized by Fourier Transform Infra Red spectroscopy, X-ray diffraction analysis, Differential scanning Calorimetry, Thermogravimetric analysis and Scanning Electron Microscopy. The aerosolisation properties of the particles were determined by using salbutamol sulfate as a model drug and compared to marketed lactose particles (RespitoseÒ ML001) used for DPI formulation.
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2. Materials and methods
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2.1. Materials
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Glyceryl monooleate (GMO, Rylo MG 19 Pharma), Salbutamol sulfate (SS) was a gift sample from Danisco culture, Denmark and Cipla Ltd. Mumbai, India respectively. Lactose monohydrate (RespitoseÒ ML001) was purchased from DFE Pharma, Germany.
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2.2. Method
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Glyceryl monooleate (GMO) was used for the preparation of gel. To describe in brief, saturated solution of lactose (20%w/v) in deionised water was prepared. GMO was melted. The molten GMO was diluted with lactose solution at 70 °C so as to obtain 35%v/v aqueous mixture of GMO. The dispersion transformed into translucent gel upon cooling. The gel became turbid when kept undisturbed for two days (48 h) indicating crystallization of lactose (LPL). The crystals so formed were recovered by addition of isopropyl alcohol which acts as a solvent for GMO and antisolvent for lactose. The suspension was filtered to obtain lactose crystals which were washed with 60% (v/v) ethanol followed by 100% (v/ v) ethanol. The crystals were allowed to dry overnight before drying in vacuum oven at 70 °C for 3 h. In order to assess reproducibility, the method was repeated twice and the lactose collected was analyzed further.
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2.3. Characterization
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2.3.1. Plane polarized light microscopy Polarized light microscopy was used to confirm the type of mesophase formed by GMO in the gel form after addition of lactose (Rosevear, 1954). Hydrated gel was transferred to a specially fabricated glass tube (internal diameter 0.5 cm) and examined for presence or absence of birefringence under a microscope at 25 ± 0.5 °C with a k/4 plate oriented at 45° to the polarizer axes under 40 magnification (Nikon Eclipse E 600, Nikon Instech Co., Japan).
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2.3.2. Small angle X-ray scattering (SAXS) In order to confirm the type of mesophase formed during crystallization of lactose, SAXS experiments were performed on a Bruker Nanostar with rotating Cu anode and pinhole geometry using a copper Ka radiation of wavelength 1.54 Å. The current
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requirement of anode was 100 mA and a potential difference of 45 kV. Lactose containing gel was taken in a quartz capillary of 2 mm diameter and 10 lm wall thickness. In order to obtain correct results background from an empty capillary was subtracted, after accounting for the sample absorption. Temperature was controlled using Bruker Peltier heating cooling unit. HISTAR gas-filled multiwire detector was used for collection of data. Scattering from the sample was measured until the scattered intensity gave at least 3 million counts on the detector. 2.3.3. Fourier transform infra-red spectroscopy (FTIR) IR spectrum for LPL and LM (RespitoseÒ ML001) were recorded using Jasco FTIR-4100 Fourier Transform Infrared Spectrophotometer (Jasco Corporation, Japan). The samples were mixed with dry potassium bromide and a total of 300 scans were collected from 4000 to 400 cm1. Jasco Spectra Manager Version 2 was used for data acquisition and analysis. 2.3.4. Thermogravimetric analysis (TGA) LPL and LM sample (30–40 mg) was placed in platinum crucibles separately and heated over a temperature range of 25–700 °C at a constant rate of 10 °C/min. Nitrogen gas was purged at flow rate of 50 ml/min in order to maintain inert atmosphere during analysis. Loss of sample mass as a function of temperature was recorded using TA-60WS Thermogravimetric analyzer (Shimandzu, Japan). 2.3.5. Differential scanning calorimetry (DSC) Calorimetric measurements were performed with Mettler Toledo 821e instrument equipped with an intracooler (Mettler Toledo, Switzerland), and calibrated with indium and zinc standards. A 10 ± 3 mg of LPL and LM sample was placed in closed aluminum crucibles separately. The crucibles were sealed and subjected to heating from 0 to 250 °C at the scanning rate of 10 °C/min. 2.3.6. X-ray powder diffraction (XRPD) X-ray diffractometer (D8 Advance, Bruker AXS Inc. Madison, USA) was used for recording XRPD patterns of LPL and LM samples. The samples were irradiated with monochromatized Cu Ka radiation (1.542 A°) and analyzed in 2h range of 2–25°.
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2.3.7. Particle size distribution Particle size was measured by Malvern Mastersizer 2000 (Malvern, UK) working on the principle of laser diffraction. Ethanol was used as dispersant for each measurement. Malvern software version 5.2 was used for data acquisition. Analysis was done in triplicate.
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2.3.8. Powder flow
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3
prepared LPL samples were coated with thin gold–palladium layer using Auto fine coater (Joel, JFC, Tokyo, Japan) after mounting on aluminum stud. Samples were then analyzed with scanning electron microscope (Jeol, JSM-6360, Tokyo, Japan) operated at 10 kv acceleration voltage. The images obtained were processed by Image J software in order to determine various shape descriptors such as elongation ratio (E = length/width) and Circularity (C), defined as the degree to which the particle is similar to a circle.
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2.3.10. In-vitro deposition study in cascade impactor Micronized SS (3.2 ± 1.1 lm) was mixed with LPL (63–90 lm fraction) in the ratio of 1:67.5 (w:w) as reported in previous literature (Kaialy and Nokhodchi, 2012d). The sequential mixing process was performed in stoppered vials placed on a cyclone mixer for 5 s till the desired ratio was obtained. The mixture was then finally blended in double cone blender for 30 min at 40 rpm. Content uniformity (SS content) of the blend was determined using UV spectrophotometry (V-530, UV/VIS spectrophotometer, JASCO International Co., Ltd. Japan) at fixed wavelength of 276 nm. Hard gelatin capsules were filled with the prepared blend manually so as to contain 492 ± 10 lg of SS in each capsule. Eight stage, nonviable Anderson cascade impactor along with a preseparator (Westech Private Instruments; model no. WP-ACISS-0289), operating at flow rate of 28.3 L/min was used to analyze dispersion behavior of the prepared powder blend. The powder samples present within capsules were aerosolized using RotahalerÒ. UV spectrophotometry method was used to analyze SS deposited at different locations of the impactor. Various aerosolisation parameters were determined. The recovered dose (RD), sum of SS collected from capsule, inhaler device, pre-separator, induction port and all stages of impactor, emitted dose (ED) i.e. amount of SS released from inhaler device which is sum of amount of SS collected at pre-separator, induction port and all stages of impactor were determined. The capacity of the formulation to be fluidised and deagglomerated in time so as to release the drug from carrier particle in order to get deposited in the appropriate level of the impinger can be measured using fine particle dose (FPD) and fine particle fraction (FPF). FPD represents the mass of drug particles that have a aerodynamic diameter 1, higher the value of E more elongated the particle and circularity indicates how closely the projected area of a particle approached a circle (Dhumal et al., 2008; Watling et al., 2010). Elongated ratio of LPL was 1.56 ± 0.06 with a circularity of about 0.69 which indicates presence of elongated and non-circular particles in LPL. Moreover, Ò the values were comparable to Respitose ML001 (P > 0.05). The reason for high E for LPL may be attributed to the crystal growth rate. The swelling of GMO might have seeded some rod-shaped lactose crystals which acted as nuclei for other lactose molecules.
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425 426 427 428 429
430 431 432
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Table 2 TGA data indicating weight loss of RespitoseÒ ML001 and LPL. Sr. no.
Sample
Onset temp. (°C)
End temp. (°C)
Weight loss (%)
1
a-LM
131.93 222.89 284.33
143.1 246.46 315.13
4.602 15.72 54.45
109.53 228.28 278.93
137.10 242.54 309.88
2.519 13.22 55.43
2
LPL
Thus some crystal faces of these nuclei might have grown faster when compared to the other faces. The viscous nature of cubic phase might have played vital role in crystallization of elongated lactose particles. In order to support our hypothesis we did scanning electron microscopy of LPL and lactose seeds separated from gel after 5 h. Images for the same are depicted in Fig. 6.
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3.8. Powder flow
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Static (CI) and dynamic methods (angle of repose) were used to determine flow properties of LPL and RespitoseÒ ML001. The values of CI and angle of repose prove an estimate of powder flow. Lower the values better is the powder flow. As revealed from Table 3, the values of CI and angle of repose for LPL and RespitoseÒ ML001 were comparable (P > 0.05). The powder flow for LPL was in the acceptable limits and thus suggested its suitability for use as a carrier in DPI.
462
3.9. Scanning electron microscopy
470
The SEM photomicrographs of lactose seeds showed rod shaped crystals whereas LPL showed elongated lactose crystals with a size in the range of 63–90 lm supporting particle size analysis data (Fig. 6). It is proven that the elongated particles are expected to travel a longer distance before impaction occurs in comparison to less elongated particles of similar mass as a result of lower relative aerodynamic diameters of the former. Moreover, the surface of LPL was smooth. The stagnant conditions rather than random fluctuations are known to have a control on crystallization. The viscous cubic phase might have provided a turbulence free homogeneous environment wherein the lactose crystals would have grown to maturity without any surface defects. Yet another reason for obtaining lactose particles with smooth surface could be attributed to the harvesting process. In the present work, the lactose crystals were initially washed with aqueous ethanol (60%v/v) followed by absolute ethanol (100%). After separation from gel traces of mother liquor might exist on the surface of lactose crystals. Thus washing with absolute ethanol will spontaneously crystallize needle shaped fine lactose crystals on surface of lactose particles. Prewashing with dilute alcohol removed most of the mother liquor from crystal surface making it smooth. However use of more dilute ethanol can lead to erosion of lactose surface. The surface smoothing effect of aqueous ethanol has been reported earlier (Zeng et al., 2001).
471
3.10. In-vitro aerosol deposition studies
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The aerosolisation properties of LPL were compared with commercial RespitoseÒ ML001 powder. Salbutamol sulfate was used as model drug for the deposition study. Micronized SS was mixed with 63–90 sieved fractions of LPL in a ratio of 1:67.5 and filled in hard gelatin capsule. The content uniformity was found to be in the range of 96.47–101.35% for the prepared batches. The percent SS recovery for both the samples was in the range of 90.85 ± 1.72–94.03 ± 1.52 (Table 4) which is within the acceptable limits (75–125%) for mass balance (Bryon et al., 1994). Formulations containing SS blended with RespitoseÒ ML001 showed RD; 462.66 ± 21.6 lg, ED; 376.97 ± 7.95 lg and %FPF;
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Table 3 Particle size, elongation ratio, circularity, CI and angle of repose of RespitoseÒ ML001 and LPL. Type of lactose Ò
Respitose ML001 LPL
Particle size (lm)
Elongation ratio#
Circularity#
CI⁄
Angle of repose⁄
68.23 ± 5.754 71.66 ± 6.274
1.60 ± 0.04 1.56 ± 0.06
0.64 ± 0.05 0.69 ± 0.04
23 ± 2 25 ± 1
38 ± 2 40 ± 1
mean ± SD, n = 50# and n = 6⁄, P > 0.05 for unpaired t-test.
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Fig. 6. SEM photomicrographs of lactose at different stages. (A) Lactose seed crystals after 5 h. (B) Fully grown lactose crystals (LPL) at 200X. (C) LPL at 2000X and (D) RespitoseÒ ML001.
Table 4 Different aerosolisation parameters obtained from deposition of salbutamol sulfate in Anderson cascade impactor. Sr. no.
Parameter
LPL
RespitoseÒ ML001
1 2 3 4
RD (lg) % Recovery⁄ ED (lg) %FPF
447 ± 27.16 90.85 ± 1.72 363.37 ± 9.99 47.44 ± 1.62
462.66 ± 21.6 94.03 ± 1.52 376.97 ± 7.95 49.36 ± 1.17
n = 3, ⁄Mean ± RSD, SD (P > 0.05) for unpaired t-test.
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49.36 ± 1.17% whereas those with LPL showed RD; 447 ± 27.16 lg, ED; 363.37 ± 9.99 lg and %FPF; 47.44 ± 1.62%. As it can be seen that all the aerosolization parameters are high (even though statistically insignificant, P > 0.05) for formulation containing RespitoseÒ ML001 when compared to LPL, such difference in aerosolisation parameters could be attributed to the fact that commercial RespitoseÒ ML001 might be containing fines generated during manufacturing. The fines might have reduced the adhesive forces between carrier surface and drug by adhering to the surface crevices and asperities of lactose carrier leading to improvement in de-agglomeration behavior of the drug (Zeng et al., 1998). The morphological features such as size, shape and surface smoothness have an impact on deposition profiles. The elongated particles exhibit small aerodynamic diameters when compared to spherical particles with identical mass or volume (Hickey, 1992). More elongated particles are expected to travel long distance before impaction and adhere more drug particles when compared to spherical particles. Additionally they are expected to experience drag forces of the air stream for longer period of time resulting in higher proportion of drug being detached from them leading to higher values of FPF. In the current work aerosolisation properties for LPL and RespitoseÒ ML001 were found to be comparable (P > 0.05). Thus it can be concluded that liquid crystalline phase (cubic) can be used for engineering of a–LM crystals in order to obtain particles with high elongation ratio, smooth surface and improved flow.
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4. Conclusion
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In the present work, suitability of liquid crystalline phase for engineering lactose particles was analyzed. Gels with cubic phase were obtained wherein in situ seeding followed by growth of lactose crystals took place. PPL microscopy and SAXS studies revealed existence of cubic mesophase within gel. Elongated lactose crystals with smooth surface were obtained as confirmed from particle size analysis, FTIR, DSC, XRD, SEM and TGA studies. The particle size and aerosolisation data for prepared lactose crystals explored their utility as a carrier in DPI. Thus it can be concluded that cubic phase
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can be used as a probe for crystal engineering of lactose particles. Further the prepared particles can be used as a carrier in dry powder inhalation formulations.
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Acknowledgements
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Dr. Sharvil Patil thank Mr. Prashant Pisal, Poona College of Pharmacy, Pune, India and Mr. Sudhir Pagire, University of Bradford, UK for assistance in thermogravimetric analysis and scanning Electron Microscopy respectively.
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