Review
Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics 1.
Introduction
2.
Solubility optimization in cocrystal development
3.
Cocrystal effects on PK
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parameters 4.
Representative case studies
5.
Conclusion
6.
Expert opinion
Ning Shan†, Miranda L Perry, David R Weyna & Michael J Zaworotko †
Thar Pharmaceuticals, Inc., Tampa, FL, USA
Introduction: Pharmaceutical cocrystallization has emerged in the past decade as a new strategy to enhance the clinical performance of orally administered drugs. A pharmaceutical cocrystal is a multi-component crystalline material in which the active pharmaceutical ingredient is in a stoichiometric ratio with a second compound that is generally a solid under ambient conditions. The resulting cocrystal exhibits different solid-state thermodynamics, leading to changes in physicochemical properties that offer the potential to significantly modify drug pharmacokinetics. Areas covered: The impact of cocrystallization upon drug pharmacokinetics has not yet been well delineated. Herein, we compile previously published data to address two salient questions: what effect does cocrystallization impart upon physicochemical properties of a drug substance and to what degree can those effects impact its pharmacokinetics. Expert opinion: Cocrystals can impact various aspects of drug pharmacokinetics, including, but not limited to, drug absorption. The diversity of solid forms offered through cocrystallization can facilitate drastic changes in solubility and pharmacokinetics. Therefore, it is unsurprising that cocrystal screening is now a routine step in early-stage drug development. With the increasing recognition of pharmaceutical cocrystals from clinical, regulatory and legal perspectives, the systematic commercialization of cocrystal containing drug products is just a matter of time. Keywords: AUC, Cmax, cocrystal, crystal engineering, drug development, pharmacokinetics, solubility, Tmax Expert Opin. Drug Metab. Toxicol. (2014) 10(9):1255-1271
1.
Introduction
Pharmacokinetics is a subdivision of pharmacology that addresses the concentrations or quantities of drug molecules and their metabolites in biological fluids, tissues and excreta as a function of time [1]. In general, pharmacokinetic (PK) studies focus upon the understanding and characterization of drug absorption, distribution, metabolism and excretion, as well as their relationships to pharmacodynamics and toxicology. Particularly, drug absorption, the transport of drug molecules from the corresponding drug substance or active pharmaceutical ingredient (API) into blood circulation, represents a critical PK process for orally administered drug products. Most APIs are solids under ambient conditions and most drug products are developed and orally delivered as solid dosage forms [2]. Oral absorption of a drug is typically a two-step process. First, the drug product dissolves into the biological fluids secreted in the gastrointestinal (GI) tract. Second, drug molecules permeate across the GI membrane via modes such as passive diffusion or active transport. Solubility and permeability are therefore two parameters that impact the efficiency of oral drug absorption. In this context, the United States FDA issued a Guidance for Industry [3] to address the need to identify and characterize solid forms of 10.1517/17425255.2014.942281 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Pharmaceutical cocrystallization emerged at the beginning of this millennium as a promising approach to enhance the clinical performance of drug products. Discovery of pharmaceutical cocrystals is facilitated by crystal engineering and the supramolecular synthon approach. Pharmaceutical cocrystals can exhibit distinctively different molecular arrangements and solid-state thermodynamics, which can in turn lead to significant changes in physicochemical and pharmacokinetic (PK) properties. The diversity of cocrystal formers available for an active pharmaceutical ingredient enables fine-tuning of its solubility and pharmacokinetics. Cocrystal PK data in the public domain are insufficient for quantitative analysis because study design and/or cocrystal characteristics can impact outcomes. While optimization of oral absorption has been a focus of literature cocrystal studies, changes of drug distribution, metabolism and excretion by cocrystallization can also occur, especially when a biologically active coformer is used.
This box summarizes key points contained in the article.
drug molecules [4] and classify orally administrated drugs, via the Biopharmaceutics Classification System (BCS) [5], according to their solubility and permeability. With respect to BCS, an API is considered highly soluble when the highest dose strength dissolves in < 250 ml of water over a pH ranging from 1 to 7.5. Also, an API is considered highly permeable when the extent of absorption in humans is determined to be > 90% of the administered dose based on mass balance or in comparison to an intravenous reference dose. It has been noted that ca. 30% of the orally administered drug products currently on the market contain APIs that belong to BCS class II (i.e., low solubility and high permeability). Moreover, ~ 70% of the new chemical entities under development, potentially for oral administration, also exhibit low solubilities [6]. With this in mind, effort has been directed toward improving the aqueous solubility of poorly soluble APIs [2,7]. The development of novel crystal forms (Figure 1) is one of the approaches that has been implemented for solubility optimization [8-10]. Crystalline APIs tend to be preferred over amorphous forms or solid solutions because of purity, stability, ease of processing and reproducibility issues [11-13]. Further, different crystal forms can exhibit different solidstate thermodynamics affecting physicochemical properties that in turn impact the clinical performance of drug products. Crystal form screening conducted to meet FDA directives [5] has the primary objective of identifying a crystalline solid that is suitable for use in a drug product and is therefore an important step at the preformulation stage of drug development. Traditionally, crystal form screening is focused upon the generation of polymorphs, salts, hydrates 1256
and solvates [14,15]. However, meta-stable polymorphs, hydrates and solvates, although acceptable for use in drug products and successfully used for certain classes of drug products [16-20], can be less stable than the thermodynamically stable single-component crystal form. In addition, single-component crystalline solids are typically limited to the most stable polymorph. Whereas salts offer greater diversity and represent ca. 50% of drug substances in currently approved drug products [21,22], not all drug molecules are suitable for salt formation because they lack ionizable functional groups or are chemically unstable at pH extremes. Cocrystals represent a class of solid forms that have been long known but are somewhat understudied [23,24]. The definition of a cocrystal has been debated in the scientific community [25,26] but today there is a consensus that a cocrystal is a multi-component crystal form that should be differentiated from salts and solvates. In the literature, a cocrystal has been defined as a multi-component crystal comprising two or more compounds that are solids under ambient conditions, present in a stoichiometric ratio and interact by noncovalent interactions such as hydrogen bonding [23,25,27,28]. A cocrystal is a pharmaceutical cocrystal when at least one API is a component and the other component(s) (i.e., cocrystal former or coformer) is a pharmaceutically acceptable compound that is a solid under ambient conditions. Cocrystals do not rely upon the presence of ionizable functional groups and extensive libraries of coformers are available. It should therefore be unsurprising that pharmaceutical cocrystals have emerged in the past decade [23,28,29] as a preformulation strategy and this is reflected by the recent issuance of an FDA Guidance for Industry concerning cocrystals [30]. Pharmaceutical cocrystal development is no longer an emerging strategy. Rather, it has established itself as a routine part of the early stages of drug development. This is due at least in part to the realization that pharmaceutical cocrystallization affords an opportunity to modify, sometimes dramatically, the physicochemical properties of an API without covalent modification of its molecular structure. Cocrystal development is particularly attractive when salt formation is infeasible or when existing salts fail to exhibit suitable properties for use in a drug product. In addition, cocrystals of pharmaceutical salts, namely ionic cocrystals [31], might also be prepared and evaluated. Further, whereas molecular cocrystals only offer one variable (i.e., the coformer), ionic cocrystals offer two variables: an ionized drug molecule can be cocrystallized with a counter ion and a coformer; a neutral drug molecule can be cocrystallized with salts that offer two counterions. In principle, this versatility could potentially enable the preparation of thousands of pharmaceutical cocrystals if so desired. A key issue in the preparation of pharmaceutical cocrystals is the selection of a library of coformers that is compatible with the target drug molecule. Ab initio prediction of the precise details
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Impact of pharmaceutical cocrystals
Single-component solid forms
Neutral API Charged API Polymorphs
Amorphous form
Coformer Salt former
Multi-component solid form – Type A
Water/solvent
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Solvent channel
Hydrates/Solvates
Channel solvate
Multi-component solid form – Type B
Salt
Cocrystal
Ionic cocrystal
Figure 1. Pharmaceutical solid forms that have been used in drug products. For multi-component solid forms, type A forms are not very amenable to design and offer limited diversity, whereas type B forms are more suited for crystal engineering studies and offer greater diversity. API: Active pharmaceutical ingredient.
of a crystal structure based solely on the knowledge of the molecular structure of a compound remains a challenge for the types of molecules typically used as APIs [32,33]. Therefore, ‘brute-force’ cocrystal screening, whereby a predetermined coformer library comprising most pharmaceutically acceptable and/or approved compounds, can be used. A high-throughput screen, often fulfilled by robotic systems, is performed according to the preprogrammed operating procedures [34]. Given the number of variables in a three or more component phase diagram, however, even high-throughput methods might not be able to explore the full landscape of crystal forms. A crystal engineering approach based upon the use of supramolecular synthons [35,36] can also be employed. As there is a design or crystal engineering element to the screening process, a key aspect of cocrystals that differentiates them from other multicomponent crystal forms such as solvates and hydrates is that there can be a control over the stoichiometry. While there can be a reasonable expectation that certain molecules are more likely than others to form hydrates and solvates [37,38], control over stoichiometry can be more difficult. The experimental aspect of pharmaceutical cocrystal screening can include multiple methods, such as solution evaporation [39], grinding [40-42], melt extrusion [43], slurry [27], microwave agitation [44] and resonant acoustic mixing [45].
Solubility optimization in cocrystal development
2.
Whereas solvates, hydrates and polymorphs typically exhibit similar solid-state thermodynamics and solubility [46], a pharmaceutical cocrystal can present very different physicochemical properties versus the parent API. Based on the available data in the literature, the impacts of pharmaceutical cocrystals upon solubility can be summarized as follows: . Enhanced diversity of solubility profiles -- That cocrystals
can be kinetically unstable or kinetically stable over a relevant time frame in aqueous media means that pharmaceutical cocrystallization can modify equilibrium solubility, dissolution profile or both. Such an ability to modulate solubility can be advantageous and is further enabled by the relatively large number of possible coformers for most APIs. The ‘cocrystal effect’ on API solubility is exemplified by a study of fluoxetine hydrochloride (Prozac) cocrystals, which reported increased solubility, decreased solubility and greatly increased solubility in a kinetically unstable cocrystal [47]. . Magnitude of solubility change -- Whereas pharmaceutical cocrystals can change drug substance solubility in
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different ways, it is also important to understand to what extent it occurs. As mentioned earlier, polymorphs and hydrates offer limited opportunities for dramatic change in solubility and tend to exhibit modest or insignificant solubility differences [46,48]. In contrast, a cocrystal can be likened to a salt since there is potential for large changes in solubility [49,50]. In some cases, it has become apparent that pharmaceutical cocrystals can even finetune drug solubility in a rational manner [51]. Moreover, it has been demonstrated that pharmaceutical cocrystals can exhibit a much more pronounced impact upon the solubility and dissolution profile of the parent API, compared to the physical mixture of the parent API and coformer [52-54]. . Lack of predictability -- When the supramolecular synthon approach is coupled with a large library of pharmaceutically acceptable or already approved coformers, effectively all APIs are amenable to cocrystal formation. What is less clear about pharmaceutical cocrystals is twofold: i) whether the solubility effect can be predicted with any degree of reliability; and ii) whether a novel cocrystal can be protected as intellectual property for drug development. Cocrystal solubility can correlate strongly with coformer solubility [55,56], but the data are too limited to draw broad conclusions about the effect of cocrystallization upon API solubility [57,58]. This lack of predictability could be useful in arguing that a novel cocrystal that exhibits a significant solubility improvement is unexpected and nonobvious. The opportunity to obtain patent protection is attractive because exclusivity might be needed to justify the costs associated with the later stages of drug development and commercialization. It is reasonable to assert that the patent landscape with respect to pharmaceutical cocrystals has nucleated and is beginning to crystallize [59].
3.
Cocrystal effects on PK parameters
In recognition of their distinct solubility characteristics, pharmaceutical cocrystals have been frequently used for the purpose of modulating drug pharmacokinetics [27,52,57,58,60,61] and the impact could be significant when solubility limits the PK process. In order to better understand how cocrystals affect drug pharmacokinetics, we have conducted a literature search on those cocrystal case studies that present PK data. We have collated cocrystal PK parameters disclosed in the scientific and patent literature and performed data analysis that enable us to draw some general conclusions concerning cocrystal effects on pharmacokinetics. PK studies in the public domain were restricted using the following criteria: i) only small molecule APIs (molecular weight of APIs < 1000 g/ mol) were selected; ii) at least one PK parameter reported for each cocrystal; and iii) same PK parameter reported for the corresponding parent API as a reference. PK parameters 1258
were limited to plasma or serum AUC, Cmax and Tmax, which are frequently reported and evaluated in pharmacological and toxicological studies [1,62-64]. Whenever available, solubility data of cocrystals and corresponding parent APIs were also collated and, if necessary, converted to API equivalent values. After data collation, it was realized that data comparison between different groups of cocrystals is difficult as there are no standards with respect to solubility and PK study protocols. Obviously, different study protocols and control experiments could produce different results, even if the same cocrystal was studied. Common variables that can influence the study results are summarized in Table 1. In order to minimize the impact of study design upon our data analysis, cocrystal solubility, AUC and Cmax data were converted to dimensionless ratios relative to the corresponding parent APIs, affording RSol (cocrystal solubility relative to parent API), RAUC (cocrystal area under curve relative to parent API) and RCmax (cocrystal peak concentration relative to parent API), respectively. We took this approach because in most studies the solubility and PK data of a cocrystal and the corresponding parent API were generated using the same protocols and study conditions. When the cocrystal and the corresponding parent API were administered at different equivalent dose strengths, RAUC and RCmax data were normalized under the assumption of dose proportionality (Table 2). Compared to AUC and Cmax, Tmax data are less abundant. Tmax could also be less well defined due to limited sampling frequency and/or complexity of the PK profile. Further, any trends with respect to Tmax changes could be masked if the cocrystal and its parent API were administered at different dose strengths. To enable comparisons among cocrystals, the change of Tmax by a cocrystal was qualitatively categorized either as an increase, decrease or similar, relative to the corresponding parent API without dose normalization. The PK and solubility data for each pharmaceutical cocrystal investigated were combined into a single data entry for subsequent analysis. Occasionally, a cocrystal was evaluated under multiple formulation and/or dosing conditions. For such cases, the PK data generated under each condition were treated as an independent entry. Eventually, 76 data entries from 64 cocrystals involving 21 API molecules were identified. Parent APIs Prior to analyzing the impact of cocrystallization upon PK parameters, we categorized the parent APIs involved in the various cocrystal PK studies based upon their BCS classes (Table 3). Twelve of the APIs studied are approved by the FDA for use in commercial drug products, whereas the remainders are investigational compounds. The BCS classification for nine of the approved APIs was obtained from the online database sponsored by Therapeutics Systems Research Laboratory, Inc. (Ann Arbor, MI). The BCS classification for the other three approved APIs (i.e., iloperideone, danazol and indomethacin) was determined based on relevant solubility and permeability classifications [65,66]. 3.1
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Impact of pharmaceutical cocrystals
Table 1. Variables in study design that can impact solubility and PK data of cocrystals. Cocrystal solubility study
Cocrystal PK study
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Dissolution study setup Study setup: apparatus type, stirring rate Dissolution medium: medium type, volume, pH, temperature Test material Drug substance (API): purity, particle size, morphology, stability Drug product: dosage form (powder, tablet, capsule etc.), excipient, vehicle, solvent, stability Sample collection: sampling time and frequency, compensation for liquid loss
Analytical chemistry Sample processing: pH control, sample extraction and/or dilution Method development: sample separation and detection Method validation: specificity, accuracy, precision, quantitation/detection limits, linear range, sample stability Data evaluation Solubility definition: bulk solubility, intrinsic solubility, solubility at equilibrium, Smax (peak concentration) Statistical analysis method
In-life study setup Biological subject selection: species, strain, sex, age, N, genetic modification Pre-dose treatment: gastric pH change Dosing design: single dosing versus multiple dosing, crossover versus non-crossover, washout period Dosing time: effect of circadian rhythms Dose level selection: HED, dose linearity/response, toxicity, analytical detection limit Formulation development Drug substance (API): purity, particle size, morphology, stability Drug product: dosage form (solid, suspension, solution), excipient, solvent, vehicle, stability Food effect: fed versus fasted, fasting period, food fat content Sample collection: sample type (plasma, serum, excreta, tissue, etc.), sampling time and frequency Bioanalytical chemistry Sample processing: pH and temperature control, sample extraction and/or dilution, sample derivatization, internal standard Method development: sample separation and detection Method validation: specificity, accuracy, precision, quantitation/detection limits, linear range, sample stability PK evaluation Compartmental versus non-compartmental analysis Method of AUC integration AUC cutoff range Considerations of terminal phase Statistical analysis
API: Active pharmaceutical ingredient; HED: Human equivalent dose; PK: Pharmacokinetic.
Specifically, the reported aqueous solubility or the lower limit of the reported aqueous solubility range was chosen to be the solubility of each API. Also, the BCS solubility classification was facilitated by the dose number (D0) of each API, which was calculated by the highest human dose of immediaterelease oral solid dosage formulations, the human uptake volume of 250 ml and the solubility of the API, as follows: (1) Highest Human Dose / Uptake Volume D0 = Solubility of API An API with a D0 £ 1 was thereby classified as highly soluble. Permeability of each API was classified from its calculated partition coefficient (CLogP) estimate, which was considered to be more available and more accurate than other predictors of partition coefficient [67]. Subsequently, an API with a CLogP value equal or greater than that of metoprolol (CLogP = 1.49) was classified as highly permeable [65]. Consequently, 10 of the approved APIs are BCS class II, 1 approved API is BCS class I (i.e., highly soluble and highly permeable), and the other is BCS class IV (i.e., poorly soluble and poorly permeable).
It should be noted that the BCS classes for approved APIs in this contribution remain provisional since classifications are based on secondary solubility references as well as CLogP correlations to human jejunal permeability [66]. The BCS classes of such APIs could ultimately be revised if more experimental data become available. We also recognized that BCS classification is defined based on human dosing information, while APIs and pharmaceutical cocrystals in the literature were administered at different dose strengths to various animals with different GI physiology. The listed BCS classes of approved APIs should be further validated against the actual dosing conditions, even though solubility criteria for drugs used in veterinary species is not yet well established [68]. To facilitate the validation, the equivalent dose number (D0’) was introduced and estimated based on the highest human equivalent dose (HED), the human uptake volume of 250 ml and the solubility of API, as follows: (2) Highest HED /Uptake Volume D0 ′ = Solubility of API
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Table 2. Relative AUC, Cmax and solubility of literature cocrystals after dose normalization. API
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AMG 517 [58,61]
Baicalein [54] Celecoxib [87]
CFPPC [72] Cilostazol [88]
Danazol [89] Dipfluzine [53] EGCG [83]
Iloperidone [90,91]
Indomethacin [70] Itraconazole HCl [92] L-883555 [93] Lamotrigine [94] Li salicylate [31,95] Meloxicam§ [76,96]
Coformer
RAUC
RCmax
RSol
2,5-Dihydroxybenzoic acid 2-Hydroxycaproic acid Adipic acid Benzamide Benzoic acid Cinnamamide Cinnamic acid Glutaric acid Glycolic acid L-Lactic acid L-Malic acid Maleic acid Malonic acid Sorbic acid (Dc: 10 mg/kg) Sorbic acid (Dc: 30 mg/kg) Sorbic acid (Dc: ~ 100 mg/kg) Sorbic acid (Dc: 100 mg/kg) Sorbic acid (Dc: 500 mg/kg) Succinic acid Trans-2-hexanoic acid Nicotinamide Tramadol HCl formulation A Tramadol HCl formulation B Tramadol HCl formulation C Glutaric acid (Dc: 5 mg/kg) Glutaric acid (Dc: 50 mg/kg) 2,4-Dihydroxybenzoic acid 4-Hydroxybenzoic acid Gentisic acid (MH) Vanillin (unformulated) Vanillin (formulated) Benzoic acid Isonicotinamide (PH) Isonicotinic acid Isonicotinic acid (TH) Nicotinamide (NH) 2,3-Dihydroxybenzoic acid 3,5-Dihydroxybenzoic acid 3-Hydroxybenzoic acid 3,5-Pyridinedicarboxylic acid Saccharin DL-Tartaric acid* z DL-Tartaric acid L-Tartaric acid Nicotinamide (MH) Nicotinamide L-Proline 1-Hydroxy-2-naphthoic acid Aspirin
4.55 4.11 3.15 6.83 4.88 7.44 2.37 6.32 7.45 2.84 7.45 6.44 6.82 28.4 25.1 7.11 15.5 9.39 5.95 5.85 2.80# 1.65 0.91 1.52 3.30 2.51 8.97 10.6 3.28 1.72 10.3 2.86 0.57 1.05 1.37 0.55 2.23 0.93 0.10 1.13 2.43 0.71 1.58 22.9 0.43 0.62 1.12 6.25 4.41
4.25 4.29 2.81 6.62 5.18 6.39 2.06 6.40 7.64 2.76 7.37 6.83 7.51 44.0 35.4 7.50 19.3 7.67 6.50 5.35 2.49# 2.90 1.46 1.62 3.51 3.12 14.6 16.7 5.78 2.95 13.6 2.05 0.37 0.49 1.02 0.55 3.93 3.11 0.27 1.24 6.25 0.80 1.02 14.7 0.46 0.64 1.13 7.03 4.58
1.67 2.83 1.17 2.33 2.00 2.17 1.67 2.67 2.33 1.67 2.33 2.17 2.67 1.32 1.32 1.83 1.32 1.32 1.83 2.50 NA NA NA NA 18.0 18.0 NA NA NA NA NA 596 0.056 0.052 0.040 0.123 NA NA NA NA 3.60 NA NA NA 0.82 1.07 NA 2.24 44.0
*Animal gastric pH was modified by pentagastrin before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. z Animal gastric pH was modified by Pepcid AC before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. § Each cocrystal was administered at a dose of 1 mg/kg meloxicam equivalent. { Each cocrystal was administered at a dose of 10 mg/kg meloxicam equivalent. Integration for cocrystal AUCs was truncated at 4 h post-dose. # PK data were calculated based on in vivo concentrations of baicalin, which is an active metabolite of baicalein. API: Active pharmaceutical ingredient; CFPPC: 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; Dc: Dose of cocrystal at API equivalent value; DH: Dihydrate; EGCG: Epigallocatechin gallate; Li: Lithium; MA: Methanolate; MH: Monohydrate; NA: Not available; NH: Nanohydrate; NXV-144: N’-(7-fluoropyrrolo[1,2a]quinoxalin-4-yl)pyrazine-2-carbohydrazide; PH: Pentahydrate; PK: Pharmacokinetic; RAUC: Cocrystal area under curve relative to parent API; RCmax: Cocrystal peak concentration relative to parent API; RSol: Cocrystal solubility relative to parent API; TH: Trihydrate.
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Table 2. Relative AUC, Cmax and solubility of literature cocrystals after dose normalization (continued). API
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Meloxicam{ [57]
Metaxalone [97] Modafinil [98] NVX-144 [99] Quercetin [50]
Tramadol HCl [87]
Coformer Maleic acid Salicylic acid form III Succinic acid 1-Hydroxy-2-naphthoic acid 4-Hydroxybenzoic acid Benzoic acid DL-Malic acid Fumaric acid Glutaric acid Glycolic acid Hydrocinnamic acid L-Malic acid Maleic acid Salicylic acid form III Succinic acid Fumaric acid Succinic acid Malonic acid Oxalic acid Caffeine Caffeine (MA) Isonicotinamide Theobromine (DH) Celecoxib formulation A Celecoxib formulation B Celecoxib formulation C
RAUC
RCmax
RSol
2.53 2.96 2.84 1.60 1.30 1.17 1.14 0.68 1.23 0.85 0.95 1.18 1.22 1.50 1.36 2.19 1.74 1.23 1.26 2.57 4.01 5.46 9.93 0.34 0.43 0.92
2.53 3.78 3.02 NA NA NA NA NA NA NA NA NA NA NA NA 1.90 1.37 1.43 1.08 2.30 9.16 4.92 2.95 0.26 0.39 0.40
1.47 1.67 1.34 2.24 1.04 1.00 1.13 1.15 0.87 1.04 1.02 0.91 1.47 1.67 1.34 NA NA 5.00 NA 1730 5540 265 422 NA NA NA
*Animal gastric pH was modified by pentagastrin before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. z Animal gastric pH was modified by Pepcid AC before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. § Each cocrystal was administered at a dose of 1 mg/kg meloxicam equivalent. { Each cocrystal was administered at a dose of 10 mg/kg meloxicam equivalent. Integration for cocrystal AUCs was truncated at 4 h post-dose. # PK data were calculated based on in vivo concentrations of baicalin, which is an active metabolite of baicalein. API: Active pharmaceutical ingredient; CFPPC: 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; Dc: Dose of cocrystal at API equivalent value; DH: Dihydrate; EGCG: Epigallocatechin gallate; Li: Lithium; MA: Methanolate; MH: Monohydrate; NA: Not available; NH: Nanohydrate; NXV-144: N’-(7-fluoropyrrolo[1,2a]quinoxalin-4-yl)pyrazine-2-carbohydrazide; PH: Pentahydrate; PK: Pharmacokinetic; RAUC: Cocrystal area under curve relative to parent API; RCmax: Cocrystal peak concentration relative to parent API; RSol: Cocrystal solubility relative to parent API; TH: Trihydrate.
The highest HED of an API was converted from the highest animal dose (parent API equivalent) used in the literature cocrystal PK study based on body surface area [69]. As a replacement of D0, D0’ was subsequently used for solubility classification. Based on the updated solubility classification, BCS classes of approved APIs remained unchanged, assuming CLogP correlations to permeability classification were similar between human and animals. The BCS classification for investigational APIs was similarly conducted. In the absence of human dosing information, HED and D0’ values were used for solubility classification. As a result, four investigational APIs are BCS class II, whereas three others are BCS class IV. In addition, two APIs are BCS class I. Statistics on BCS classification of parent APIs involved in cocrystal PK studies are presented in Figure 2A. Among all APIs involved in cocrystal PK studies, 67% belong to BCS class II while only 14 and 19% of APIs are BCS class I and IV, respectively. Statistics on cocrystal data entries categorized by the BCS classification of their corresponding parent APIs
was also performed (Figure 2B). Among the 76 data entries, 80% involve APIs from BCS class II, while only 9% involve APIs from BCS class IV. The bias toward BCS class II is consistent with the motivation for most cocrystal studies, that is, solubility optimization. To the best of our knowledge, cocrystal PK data relevant to APIs of BCS class III (i.e., highly soluble and poorly permeable) have not yet been reported. Cocrystal AUC and Cmax RAUC and RCmax can be conveniently converted to the fold changes of AUC and Cmax of APIs (Figure 3). Among 75 data entries with RAUC values, the fold-changes of AUC varied from ca. 10.2-fold decrease to ca. 28.4-fold increase. AUC decreases exist in ca. 19% of entries with RAUC data, most of which exhibit an AUC decrease of twofold or less. On the other hand, 47% of entries exhibit an AUC increase of fourfold or less, while only 8% of entries exhibit an AUC increase of 10-fold or more. The effect of cocrystallization on Cmax can also be analyzed. Among 63 entries with RCmax 3.2
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Table 3. APIs involved in literature cocrystal PK studies.
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Parent APIs
Solubility (mg/ml)
Approved APIs Carbamazepine Celecoxib Cilostazol Danazol Iloperidone Indomethacin Itraconazole Lamotrigine Meloxicam Metaxalone Modafinil Tramadol HCl
0.01 0.01 0.01 0.001 0.012 0.0095 0.01 0.17 0.01 0.1 0.01 33
Investigational APIs AMG 517 Baicalein CFPPC Dipfluzine EGCG Lithium salicylate L-883555 NVX-144 Quercetin
0.022 0.017 0.0001 0.00027 23.6 33 0.0075 0.019 0.0026
Animal dose in literature PK studies‡
FDA-approved human dose*
CLogP§
BCS class
HD (mg)
D0
Species
HD (mg/kg)
HED (mg)
D0’
400 400 100 200 12 50 200 200 15 800 200 50
160 160 40 800 4 21 40 4.7 6 32 80 0.006
Dog Dog Dog Rat Dog Dog Dog Rat Rat Dog Dog Dog
20 11.2 10 20 0.4 2.5 2.5 10 10 21 20 8.8
667 373 333 194 13 83 83 97 97 700 667 293
267 149 133 774 4.4 35 33 2.3 39 28 267 0.036
2.38 4.37 3.53 3.93 3.92 4.18 6.05 2.38 2.29 2.15 0.94 3.10
II II II II II II II II II II IV I
Rat Rat Dog Rat Rat Rat Monkey Rat Rat
500 121 50 40 100 576 3 20 100
4839 1171 1667 387 968 5576 58 194 968
880 278 66666 5714 0.16 0.68 31 41 1472
4.63 3.00 4.18 5.93 1.49 NA -0.49 1.36 1.30
II II II II I I IV IV IV
*Highest human doses of immediate-release oral solid dosage formulations were obtained from the FDA Orange Book (updated in May 2013). z For calculation purpose, the body weights of rat, dog and human were assumed to be 0.25, 10 and 60 kg, respectively, unless otherwise specified in the study. When the range of animal body weights was provided in the study, the median was used for calculation. § CLogP values were estimated by the ChemDraw Ultra 8.0 program. The chemical structures used for estimation were the uncharged forms. The CLogP value for lithium salts could not be obtained, while lithium salts were treated as a highly permeable API. API: Active pharmaceutical ingredient; BCS: Biopharmaceutics classification system; CFPPC: 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; CLogP: Calculated partition coefficient; D0: Dose number based on highest human dose; D0’: Equivalent dose number based on highest HED; EGCG: Epigallocatechin gallate; HD: Highest dose; HED: Human equivalent dose; NA: Not available; PK: Pharmacokinetic.
data, the fold changes of Cmax range from an approximately fourfold decrease to a 44-fold increase. Overall, 52% of entries with RCmax values are accompanied by a less than sixfold Cmax increase by cocrystallization. Interestingly, AUC and Cmax changes exhibited by a cocrystal might not be achieved by the physical mixture of the corresponding API and coformer [54,70]. Correlation between RAUC and RCmax can also be evaluated. Before data comparison, both dimensionless parameters were subjected to a natural logarithmic transformation, thereby enabling us to distribute the resulting LnRAUC and LnRCmax on a symmetric scale [71]. The logarithmic transformation also facilitates a qualitative analysis of relative PK and solubility data. For example, a positive value of LnRAUC corresponds to an AUC increase affected by cocrystallization, while a negative LnRAUC reflects a decrease in AUC. An LnRAUC of zero means that there is no effect of cocrystallization on AUC. A relatively strong linear correlation (R2 = 0.88) is observed in the plot of LnRAUC versus LnRCmax (Figure 3C). Quantitatively, relative AUC and Cmax changes 1262
by a cocrystal are comparable on the logarithmic scale, as evidenced by the slope of the regression line. Based on the strong correlation of this plot and the number of data points, it is reasonable to assert that correlation of RAUC and RCmax is a general artifact of cocrystallization. Since the ‘cocrystal effect’ upon bioavailability has often been attributed to changes in RSol, the potential AUC increase by cocrystallization was correlated to the aqueous solubility of the parent API. All 20 APIs with RAUC data are included in our analysis. For each parent API, the potential AUC increase by cocrystallization is represented by the maximal RAUC exhibited by its cocrystals (i.e., RAUCmax). In order to account for variation of dose strength, D0’ is used as a quantitative solubility measure for each parent API. After natural logarithmic transformation, D0’ and RAUCmax data were plotted (Figure 4). In general, a higher D0’ correlates to a greater value of RAUCmax, indicating that a higher RAUC value is generally associated with a parent API that exhibits relatively low solubility. Solubility increase by cocrystallization would be expected to have less impact
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Impact of pharmaceutical cocrystals
API distribution
A.
B.
Entries with investigational APIs (BCS IV) 7.9%
Approved APIs (BCS I) 4.8%
Investigational APIs (BCS IV) 14.3%
Entries with approved APIs (BCS I) 3.9%
Entries with investigational APIs (BCS II) 31.6%
Investigational APIs (BCS II) 19.0%
Entries with approved APIs (BCS II) 48.7%
Approved APIs (BCS II) 47.6%
Investigational APIs (BCS I) 9.5%
Entries with investigational APIs (BCS I) 6.6%
Approved APIs (BCS IV) 4.8%
Entries with approved APIs (BCS IV) 1.3%
Figure 2. A. Statistics on BCS classification of parent APIs involved in literature cocrystal PK studies (n = 21). B. Statistics on cocrystal data entries categorized by the BCS classification of their corresponding parent APIs (n = 76). API: Active pharmaceutical ingredient; BCS: Biopharmaceutics classification system; PK: Pharmacokinetic.
A.
B. 20
10 AUC
15
AUC Count number
Count number
Cmax
10 5 0
1
≤
2 FI
Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics 1.
Introduction
2.
Solubility optimization in cocrystal development
3.
Cocrystal effects on PK
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parameters 4.
Representative case studies
5.
Conclusion
6.
Expert opinion
Ning Shan†, Miranda L Perry, David R Weyna & Michael J Zaworotko †
Thar Pharmaceuticals, Inc., Tampa, FL, USA
Introduction: Pharmaceutical cocrystallization has emerged in the past decade as a new strategy to enhance the clinical performance of orally administered drugs. A pharmaceutical cocrystal is a multi-component crystalline material in which the active pharmaceutical ingredient is in a stoichiometric ratio with a second compound that is generally a solid under ambient conditions. The resulting cocrystal exhibits different solid-state thermodynamics, leading to changes in physicochemical properties that offer the potential to significantly modify drug pharmacokinetics. Areas covered: The impact of cocrystallization upon drug pharmacokinetics has not yet been well delineated. Herein, we compile previously published data to address two salient questions: what effect does cocrystallization impart upon physicochemical properties of a drug substance and to what degree can those effects impact its pharmacokinetics. Expert opinion: Cocrystals can impact various aspects of drug pharmacokinetics, including, but not limited to, drug absorption. The diversity of solid forms offered through cocrystallization can facilitate drastic changes in solubility and pharmacokinetics. Therefore, it is unsurprising that cocrystal screening is now a routine step in early-stage drug development. With the increasing recognition of pharmaceutical cocrystals from clinical, regulatory and legal perspectives, the systematic commercialization of cocrystal containing drug products is just a matter of time. Keywords: AUC, Cmax, cocrystal, crystal engineering, drug development, pharmacokinetics, solubility, Tmax Expert Opin. Drug Metab. Toxicol. (2014) 10(9):1255-1271
1.
Introduction
Pharmacokinetics is a subdivision of pharmacology that addresses the concentrations or quantities of drug molecules and their metabolites in biological fluids, tissues and excreta as a function of time [1]. In general, pharmacokinetic (PK) studies focus upon the understanding and characterization of drug absorption, distribution, metabolism and excretion, as well as their relationships to pharmacodynamics and toxicology. Particularly, drug absorption, the transport of drug molecules from the corresponding drug substance or active pharmaceutical ingredient (API) into blood circulation, represents a critical PK process for orally administered drug products. Most APIs are solids under ambient conditions and most drug products are developed and orally delivered as solid dosage forms [2]. Oral absorption of a drug is typically a two-step process. First, the drug product dissolves into the biological fluids secreted in the gastrointestinal (GI) tract. Second, drug molecules permeate across the GI membrane via modes such as passive diffusion or active transport. Solubility and permeability are therefore two parameters that impact the efficiency of oral drug absorption. In this context, the United States FDA issued a Guidance for Industry [3] to address the need to identify and characterize solid forms of 10.1517/17425255.2014.942281 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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Pharmaceutical cocrystallization emerged at the beginning of this millennium as a promising approach to enhance the clinical performance of drug products. Discovery of pharmaceutical cocrystals is facilitated by crystal engineering and the supramolecular synthon approach. Pharmaceutical cocrystals can exhibit distinctively different molecular arrangements and solid-state thermodynamics, which can in turn lead to significant changes in physicochemical and pharmacokinetic (PK) properties. The diversity of cocrystal formers available for an active pharmaceutical ingredient enables fine-tuning of its solubility and pharmacokinetics. Cocrystal PK data in the public domain are insufficient for quantitative analysis because study design and/or cocrystal characteristics can impact outcomes. While optimization of oral absorption has been a focus of literature cocrystal studies, changes of drug distribution, metabolism and excretion by cocrystallization can also occur, especially when a biologically active coformer is used.
This box summarizes key points contained in the article.
drug molecules [4] and classify orally administrated drugs, via the Biopharmaceutics Classification System (BCS) [5], according to their solubility and permeability. With respect to BCS, an API is considered highly soluble when the highest dose strength dissolves in < 250 ml of water over a pH ranging from 1 to 7.5. Also, an API is considered highly permeable when the extent of absorption in humans is determined to be > 90% of the administered dose based on mass balance or in comparison to an intravenous reference dose. It has been noted that ca. 30% of the orally administered drug products currently on the market contain APIs that belong to BCS class II (i.e., low solubility and high permeability). Moreover, ~ 70% of the new chemical entities under development, potentially for oral administration, also exhibit low solubilities [6]. With this in mind, effort has been directed toward improving the aqueous solubility of poorly soluble APIs [2,7]. The development of novel crystal forms (Figure 1) is one of the approaches that has been implemented for solubility optimization [8-10]. Crystalline APIs tend to be preferred over amorphous forms or solid solutions because of purity, stability, ease of processing and reproducibility issues [11-13]. Further, different crystal forms can exhibit different solidstate thermodynamics affecting physicochemical properties that in turn impact the clinical performance of drug products. Crystal form screening conducted to meet FDA directives [5] has the primary objective of identifying a crystalline solid that is suitable for use in a drug product and is therefore an important step at the preformulation stage of drug development. Traditionally, crystal form screening is focused upon the generation of polymorphs, salts, hydrates 1256
and solvates [14,15]. However, meta-stable polymorphs, hydrates and solvates, although acceptable for use in drug products and successfully used for certain classes of drug products [16-20], can be less stable than the thermodynamically stable single-component crystal form. In addition, single-component crystalline solids are typically limited to the most stable polymorph. Whereas salts offer greater diversity and represent ca. 50% of drug substances in currently approved drug products [21,22], not all drug molecules are suitable for salt formation because they lack ionizable functional groups or are chemically unstable at pH extremes. Cocrystals represent a class of solid forms that have been long known but are somewhat understudied [23,24]. The definition of a cocrystal has been debated in the scientific community [25,26] but today there is a consensus that a cocrystal is a multi-component crystal form that should be differentiated from salts and solvates. In the literature, a cocrystal has been defined as a multi-component crystal comprising two or more compounds that are solids under ambient conditions, present in a stoichiometric ratio and interact by noncovalent interactions such as hydrogen bonding [23,25,27,28]. A cocrystal is a pharmaceutical cocrystal when at least one API is a component and the other component(s) (i.e., cocrystal former or coformer) is a pharmaceutically acceptable compound that is a solid under ambient conditions. Cocrystals do not rely upon the presence of ionizable functional groups and extensive libraries of coformers are available. It should therefore be unsurprising that pharmaceutical cocrystals have emerged in the past decade [23,28,29] as a preformulation strategy and this is reflected by the recent issuance of an FDA Guidance for Industry concerning cocrystals [30]. Pharmaceutical cocrystal development is no longer an emerging strategy. Rather, it has established itself as a routine part of the early stages of drug development. This is due at least in part to the realization that pharmaceutical cocrystallization affords an opportunity to modify, sometimes dramatically, the physicochemical properties of an API without covalent modification of its molecular structure. Cocrystal development is particularly attractive when salt formation is infeasible or when existing salts fail to exhibit suitable properties for use in a drug product. In addition, cocrystals of pharmaceutical salts, namely ionic cocrystals [31], might also be prepared and evaluated. Further, whereas molecular cocrystals only offer one variable (i.e., the coformer), ionic cocrystals offer two variables: an ionized drug molecule can be cocrystallized with a counter ion and a coformer; a neutral drug molecule can be cocrystallized with salts that offer two counterions. In principle, this versatility could potentially enable the preparation of thousands of pharmaceutical cocrystals if so desired. A key issue in the preparation of pharmaceutical cocrystals is the selection of a library of coformers that is compatible with the target drug molecule. Ab initio prediction of the precise details
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Impact of pharmaceutical cocrystals
Single-component solid forms
Neutral API Charged API Polymorphs
Amorphous form
Coformer Salt former
Multi-component solid form – Type A
Water/solvent
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Solvent channel
Hydrates/Solvates
Channel solvate
Multi-component solid form – Type B
Salt
Cocrystal
Ionic cocrystal
Figure 1. Pharmaceutical solid forms that have been used in drug products. For multi-component solid forms, type A forms are not very amenable to design and offer limited diversity, whereas type B forms are more suited for crystal engineering studies and offer greater diversity. API: Active pharmaceutical ingredient.
of a crystal structure based solely on the knowledge of the molecular structure of a compound remains a challenge for the types of molecules typically used as APIs [32,33]. Therefore, ‘brute-force’ cocrystal screening, whereby a predetermined coformer library comprising most pharmaceutically acceptable and/or approved compounds, can be used. A high-throughput screen, often fulfilled by robotic systems, is performed according to the preprogrammed operating procedures [34]. Given the number of variables in a three or more component phase diagram, however, even high-throughput methods might not be able to explore the full landscape of crystal forms. A crystal engineering approach based upon the use of supramolecular synthons [35,36] can also be employed. As there is a design or crystal engineering element to the screening process, a key aspect of cocrystals that differentiates them from other multicomponent crystal forms such as solvates and hydrates is that there can be a control over the stoichiometry. While there can be a reasonable expectation that certain molecules are more likely than others to form hydrates and solvates [37,38], control over stoichiometry can be more difficult. The experimental aspect of pharmaceutical cocrystal screening can include multiple methods, such as solution evaporation [39], grinding [40-42], melt extrusion [43], slurry [27], microwave agitation [44] and resonant acoustic mixing [45].
Solubility optimization in cocrystal development
2.
Whereas solvates, hydrates and polymorphs typically exhibit similar solid-state thermodynamics and solubility [46], a pharmaceutical cocrystal can present very different physicochemical properties versus the parent API. Based on the available data in the literature, the impacts of pharmaceutical cocrystals upon solubility can be summarized as follows: . Enhanced diversity of solubility profiles -- That cocrystals
can be kinetically unstable or kinetically stable over a relevant time frame in aqueous media means that pharmaceutical cocrystallization can modify equilibrium solubility, dissolution profile or both. Such an ability to modulate solubility can be advantageous and is further enabled by the relatively large number of possible coformers for most APIs. The ‘cocrystal effect’ on API solubility is exemplified by a study of fluoxetine hydrochloride (Prozac) cocrystals, which reported increased solubility, decreased solubility and greatly increased solubility in a kinetically unstable cocrystal [47]. . Magnitude of solubility change -- Whereas pharmaceutical cocrystals can change drug substance solubility in
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different ways, it is also important to understand to what extent it occurs. As mentioned earlier, polymorphs and hydrates offer limited opportunities for dramatic change in solubility and tend to exhibit modest or insignificant solubility differences [46,48]. In contrast, a cocrystal can be likened to a salt since there is potential for large changes in solubility [49,50]. In some cases, it has become apparent that pharmaceutical cocrystals can even finetune drug solubility in a rational manner [51]. Moreover, it has been demonstrated that pharmaceutical cocrystals can exhibit a much more pronounced impact upon the solubility and dissolution profile of the parent API, compared to the physical mixture of the parent API and coformer [52-54]. . Lack of predictability -- When the supramolecular synthon approach is coupled with a large library of pharmaceutically acceptable or already approved coformers, effectively all APIs are amenable to cocrystal formation. What is less clear about pharmaceutical cocrystals is twofold: i) whether the solubility effect can be predicted with any degree of reliability; and ii) whether a novel cocrystal can be protected as intellectual property for drug development. Cocrystal solubility can correlate strongly with coformer solubility [55,56], but the data are too limited to draw broad conclusions about the effect of cocrystallization upon API solubility [57,58]. This lack of predictability could be useful in arguing that a novel cocrystal that exhibits a significant solubility improvement is unexpected and nonobvious. The opportunity to obtain patent protection is attractive because exclusivity might be needed to justify the costs associated with the later stages of drug development and commercialization. It is reasonable to assert that the patent landscape with respect to pharmaceutical cocrystals has nucleated and is beginning to crystallize [59].
3.
Cocrystal effects on PK parameters
In recognition of their distinct solubility characteristics, pharmaceutical cocrystals have been frequently used for the purpose of modulating drug pharmacokinetics [27,52,57,58,60,61] and the impact could be significant when solubility limits the PK process. In order to better understand how cocrystals affect drug pharmacokinetics, we have conducted a literature search on those cocrystal case studies that present PK data. We have collated cocrystal PK parameters disclosed in the scientific and patent literature and performed data analysis that enable us to draw some general conclusions concerning cocrystal effects on pharmacokinetics. PK studies in the public domain were restricted using the following criteria: i) only small molecule APIs (molecular weight of APIs < 1000 g/ mol) were selected; ii) at least one PK parameter reported for each cocrystal; and iii) same PK parameter reported for the corresponding parent API as a reference. PK parameters 1258
were limited to plasma or serum AUC, Cmax and Tmax, which are frequently reported and evaluated in pharmacological and toxicological studies [1,62-64]. Whenever available, solubility data of cocrystals and corresponding parent APIs were also collated and, if necessary, converted to API equivalent values. After data collation, it was realized that data comparison between different groups of cocrystals is difficult as there are no standards with respect to solubility and PK study protocols. Obviously, different study protocols and control experiments could produce different results, even if the same cocrystal was studied. Common variables that can influence the study results are summarized in Table 1. In order to minimize the impact of study design upon our data analysis, cocrystal solubility, AUC and Cmax data were converted to dimensionless ratios relative to the corresponding parent APIs, affording RSol (cocrystal solubility relative to parent API), RAUC (cocrystal area under curve relative to parent API) and RCmax (cocrystal peak concentration relative to parent API), respectively. We took this approach because in most studies the solubility and PK data of a cocrystal and the corresponding parent API were generated using the same protocols and study conditions. When the cocrystal and the corresponding parent API were administered at different equivalent dose strengths, RAUC and RCmax data were normalized under the assumption of dose proportionality (Table 2). Compared to AUC and Cmax, Tmax data are less abundant. Tmax could also be less well defined due to limited sampling frequency and/or complexity of the PK profile. Further, any trends with respect to Tmax changes could be masked if the cocrystal and its parent API were administered at different dose strengths. To enable comparisons among cocrystals, the change of Tmax by a cocrystal was qualitatively categorized either as an increase, decrease or similar, relative to the corresponding parent API without dose normalization. The PK and solubility data for each pharmaceutical cocrystal investigated were combined into a single data entry for subsequent analysis. Occasionally, a cocrystal was evaluated under multiple formulation and/or dosing conditions. For such cases, the PK data generated under each condition were treated as an independent entry. Eventually, 76 data entries from 64 cocrystals involving 21 API molecules were identified. Parent APIs Prior to analyzing the impact of cocrystallization upon PK parameters, we categorized the parent APIs involved in the various cocrystal PK studies based upon their BCS classes (Table 3). Twelve of the APIs studied are approved by the FDA for use in commercial drug products, whereas the remainders are investigational compounds. The BCS classification for nine of the approved APIs was obtained from the online database sponsored by Therapeutics Systems Research Laboratory, Inc. (Ann Arbor, MI). The BCS classification for the other three approved APIs (i.e., iloperideone, danazol and indomethacin) was determined based on relevant solubility and permeability classifications [65,66]. 3.1
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Impact of pharmaceutical cocrystals
Table 1. Variables in study design that can impact solubility and PK data of cocrystals. Cocrystal solubility study
Cocrystal PK study
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Dissolution study setup Study setup: apparatus type, stirring rate Dissolution medium: medium type, volume, pH, temperature Test material Drug substance (API): purity, particle size, morphology, stability Drug product: dosage form (powder, tablet, capsule etc.), excipient, vehicle, solvent, stability Sample collection: sampling time and frequency, compensation for liquid loss
Analytical chemistry Sample processing: pH control, sample extraction and/or dilution Method development: sample separation and detection Method validation: specificity, accuracy, precision, quantitation/detection limits, linear range, sample stability Data evaluation Solubility definition: bulk solubility, intrinsic solubility, solubility at equilibrium, Smax (peak concentration) Statistical analysis method
In-life study setup Biological subject selection: species, strain, sex, age, N, genetic modification Pre-dose treatment: gastric pH change Dosing design: single dosing versus multiple dosing, crossover versus non-crossover, washout period Dosing time: effect of circadian rhythms Dose level selection: HED, dose linearity/response, toxicity, analytical detection limit Formulation development Drug substance (API): purity, particle size, morphology, stability Drug product: dosage form (solid, suspension, solution), excipient, solvent, vehicle, stability Food effect: fed versus fasted, fasting period, food fat content Sample collection: sample type (plasma, serum, excreta, tissue, etc.), sampling time and frequency Bioanalytical chemistry Sample processing: pH and temperature control, sample extraction and/or dilution, sample derivatization, internal standard Method development: sample separation and detection Method validation: specificity, accuracy, precision, quantitation/detection limits, linear range, sample stability PK evaluation Compartmental versus non-compartmental analysis Method of AUC integration AUC cutoff range Considerations of terminal phase Statistical analysis
API: Active pharmaceutical ingredient; HED: Human equivalent dose; PK: Pharmacokinetic.
Specifically, the reported aqueous solubility or the lower limit of the reported aqueous solubility range was chosen to be the solubility of each API. Also, the BCS solubility classification was facilitated by the dose number (D0) of each API, which was calculated by the highest human dose of immediaterelease oral solid dosage formulations, the human uptake volume of 250 ml and the solubility of the API, as follows: (1) Highest Human Dose / Uptake Volume D0 = Solubility of API An API with a D0 £ 1 was thereby classified as highly soluble. Permeability of each API was classified from its calculated partition coefficient (CLogP) estimate, which was considered to be more available and more accurate than other predictors of partition coefficient [67]. Subsequently, an API with a CLogP value equal or greater than that of metoprolol (CLogP = 1.49) was classified as highly permeable [65]. Consequently, 10 of the approved APIs are BCS class II, 1 approved API is BCS class I (i.e., highly soluble and highly permeable), and the other is BCS class IV (i.e., poorly soluble and poorly permeable).
It should be noted that the BCS classes for approved APIs in this contribution remain provisional since classifications are based on secondary solubility references as well as CLogP correlations to human jejunal permeability [66]. The BCS classes of such APIs could ultimately be revised if more experimental data become available. We also recognized that BCS classification is defined based on human dosing information, while APIs and pharmaceutical cocrystals in the literature were administered at different dose strengths to various animals with different GI physiology. The listed BCS classes of approved APIs should be further validated against the actual dosing conditions, even though solubility criteria for drugs used in veterinary species is not yet well established [68]. To facilitate the validation, the equivalent dose number (D0’) was introduced and estimated based on the highest human equivalent dose (HED), the human uptake volume of 250 ml and the solubility of API, as follows: (2) Highest HED /Uptake Volume D0 ′ = Solubility of API
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Table 2. Relative AUC, Cmax and solubility of literature cocrystals after dose normalization. API
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AMG 517 [58,61]
Baicalein [54] Celecoxib [87]
CFPPC [72] Cilostazol [88]
Danazol [89] Dipfluzine [53] EGCG [83]
Iloperidone [90,91]
Indomethacin [70] Itraconazole HCl [92] L-883555 [93] Lamotrigine [94] Li salicylate [31,95] Meloxicam§ [76,96]
Coformer
RAUC
RCmax
RSol
2,5-Dihydroxybenzoic acid 2-Hydroxycaproic acid Adipic acid Benzamide Benzoic acid Cinnamamide Cinnamic acid Glutaric acid Glycolic acid L-Lactic acid L-Malic acid Maleic acid Malonic acid Sorbic acid (Dc: 10 mg/kg) Sorbic acid (Dc: 30 mg/kg) Sorbic acid (Dc: ~ 100 mg/kg) Sorbic acid (Dc: 100 mg/kg) Sorbic acid (Dc: 500 mg/kg) Succinic acid Trans-2-hexanoic acid Nicotinamide Tramadol HCl formulation A Tramadol HCl formulation B Tramadol HCl formulation C Glutaric acid (Dc: 5 mg/kg) Glutaric acid (Dc: 50 mg/kg) 2,4-Dihydroxybenzoic acid 4-Hydroxybenzoic acid Gentisic acid (MH) Vanillin (unformulated) Vanillin (formulated) Benzoic acid Isonicotinamide (PH) Isonicotinic acid Isonicotinic acid (TH) Nicotinamide (NH) 2,3-Dihydroxybenzoic acid 3,5-Dihydroxybenzoic acid 3-Hydroxybenzoic acid 3,5-Pyridinedicarboxylic acid Saccharin DL-Tartaric acid* z DL-Tartaric acid L-Tartaric acid Nicotinamide (MH) Nicotinamide L-Proline 1-Hydroxy-2-naphthoic acid Aspirin
4.55 4.11 3.15 6.83 4.88 7.44 2.37 6.32 7.45 2.84 7.45 6.44 6.82 28.4 25.1 7.11 15.5 9.39 5.95 5.85 2.80# 1.65 0.91 1.52 3.30 2.51 8.97 10.6 3.28 1.72 10.3 2.86 0.57 1.05 1.37 0.55 2.23 0.93 0.10 1.13 2.43 0.71 1.58 22.9 0.43 0.62 1.12 6.25 4.41
4.25 4.29 2.81 6.62 5.18 6.39 2.06 6.40 7.64 2.76 7.37 6.83 7.51 44.0 35.4 7.50 19.3 7.67 6.50 5.35 2.49# 2.90 1.46 1.62 3.51 3.12 14.6 16.7 5.78 2.95 13.6 2.05 0.37 0.49 1.02 0.55 3.93 3.11 0.27 1.24 6.25 0.80 1.02 14.7 0.46 0.64 1.13 7.03 4.58
1.67 2.83 1.17 2.33 2.00 2.17 1.67 2.67 2.33 1.67 2.33 2.17 2.67 1.32 1.32 1.83 1.32 1.32 1.83 2.50 NA NA NA NA 18.0 18.0 NA NA NA NA NA 596 0.056 0.052 0.040 0.123 NA NA NA NA 3.60 NA NA NA 0.82 1.07 NA 2.24 44.0
*Animal gastric pH was modified by pentagastrin before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. z Animal gastric pH was modified by Pepcid AC before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. § Each cocrystal was administered at a dose of 1 mg/kg meloxicam equivalent. { Each cocrystal was administered at a dose of 10 mg/kg meloxicam equivalent. Integration for cocrystal AUCs was truncated at 4 h post-dose. # PK data were calculated based on in vivo concentrations of baicalin, which is an active metabolite of baicalein. API: Active pharmaceutical ingredient; CFPPC: 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; Dc: Dose of cocrystal at API equivalent value; DH: Dihydrate; EGCG: Epigallocatechin gallate; Li: Lithium; MA: Methanolate; MH: Monohydrate; NA: Not available; NH: Nanohydrate; NXV-144: N’-(7-fluoropyrrolo[1,2a]quinoxalin-4-yl)pyrazine-2-carbohydrazide; PH: Pentahydrate; PK: Pharmacokinetic; RAUC: Cocrystal area under curve relative to parent API; RCmax: Cocrystal peak concentration relative to parent API; RSol: Cocrystal solubility relative to parent API; TH: Trihydrate.
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Table 2. Relative AUC, Cmax and solubility of literature cocrystals after dose normalization (continued). API
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Meloxicam{ [57]
Metaxalone [97] Modafinil [98] NVX-144 [99] Quercetin [50]
Tramadol HCl [87]
Coformer Maleic acid Salicylic acid form III Succinic acid 1-Hydroxy-2-naphthoic acid 4-Hydroxybenzoic acid Benzoic acid DL-Malic acid Fumaric acid Glutaric acid Glycolic acid Hydrocinnamic acid L-Malic acid Maleic acid Salicylic acid form III Succinic acid Fumaric acid Succinic acid Malonic acid Oxalic acid Caffeine Caffeine (MA) Isonicotinamide Theobromine (DH) Celecoxib formulation A Celecoxib formulation B Celecoxib formulation C
RAUC
RCmax
RSol
2.53 2.96 2.84 1.60 1.30 1.17 1.14 0.68 1.23 0.85 0.95 1.18 1.22 1.50 1.36 2.19 1.74 1.23 1.26 2.57 4.01 5.46 9.93 0.34 0.43 0.92
2.53 3.78 3.02 NA NA NA NA NA NA NA NA NA NA NA NA 1.90 1.37 1.43 1.08 2.30 9.16 4.92 2.95 0.26 0.39 0.40
1.47 1.67 1.34 2.24 1.04 1.00 1.13 1.15 0.87 1.04 1.02 0.91 1.47 1.67 1.34 NA NA 5.00 NA 1730 5540 265 422 NA NA NA
*Animal gastric pH was modified by pentagastrin before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. z Animal gastric pH was modified by Pepcid AC before dosing. Sporanox (Itraconazole) was used as the reference parent API for cocrystal relative AUC and Cmax calculations. § Each cocrystal was administered at a dose of 1 mg/kg meloxicam equivalent. { Each cocrystal was administered at a dose of 10 mg/kg meloxicam equivalent. Integration for cocrystal AUCs was truncated at 4 h post-dose. # PK data were calculated based on in vivo concentrations of baicalin, which is an active metabolite of baicalein. API: Active pharmaceutical ingredient; CFPPC: 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; Dc: Dose of cocrystal at API equivalent value; DH: Dihydrate; EGCG: Epigallocatechin gallate; Li: Lithium; MA: Methanolate; MH: Monohydrate; NA: Not available; NH: Nanohydrate; NXV-144: N’-(7-fluoropyrrolo[1,2a]quinoxalin-4-yl)pyrazine-2-carbohydrazide; PH: Pentahydrate; PK: Pharmacokinetic; RAUC: Cocrystal area under curve relative to parent API; RCmax: Cocrystal peak concentration relative to parent API; RSol: Cocrystal solubility relative to parent API; TH: Trihydrate.
The highest HED of an API was converted from the highest animal dose (parent API equivalent) used in the literature cocrystal PK study based on body surface area [69]. As a replacement of D0, D0’ was subsequently used for solubility classification. Based on the updated solubility classification, BCS classes of approved APIs remained unchanged, assuming CLogP correlations to permeability classification were similar between human and animals. The BCS classification for investigational APIs was similarly conducted. In the absence of human dosing information, HED and D0’ values were used for solubility classification. As a result, four investigational APIs are BCS class II, whereas three others are BCS class IV. In addition, two APIs are BCS class I. Statistics on BCS classification of parent APIs involved in cocrystal PK studies are presented in Figure 2A. Among all APIs involved in cocrystal PK studies, 67% belong to BCS class II while only 14 and 19% of APIs are BCS class I and IV, respectively. Statistics on cocrystal data entries categorized by the BCS classification of their corresponding parent APIs
was also performed (Figure 2B). Among the 76 data entries, 80% involve APIs from BCS class II, while only 9% involve APIs from BCS class IV. The bias toward BCS class II is consistent with the motivation for most cocrystal studies, that is, solubility optimization. To the best of our knowledge, cocrystal PK data relevant to APIs of BCS class III (i.e., highly soluble and poorly permeable) have not yet been reported. Cocrystal AUC and Cmax RAUC and RCmax can be conveniently converted to the fold changes of AUC and Cmax of APIs (Figure 3). Among 75 data entries with RAUC values, the fold-changes of AUC varied from ca. 10.2-fold decrease to ca. 28.4-fold increase. AUC decreases exist in ca. 19% of entries with RAUC data, most of which exhibit an AUC decrease of twofold or less. On the other hand, 47% of entries exhibit an AUC increase of fourfold or less, while only 8% of entries exhibit an AUC increase of 10-fold or more. The effect of cocrystallization on Cmax can also be analyzed. Among 63 entries with RCmax 3.2
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Table 3. APIs involved in literature cocrystal PK studies.
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Gazi Univ. on 08/20/14 For personal use only.
Parent APIs
Solubility (mg/ml)
Approved APIs Carbamazepine Celecoxib Cilostazol Danazol Iloperidone Indomethacin Itraconazole Lamotrigine Meloxicam Metaxalone Modafinil Tramadol HCl
0.01 0.01 0.01 0.001 0.012 0.0095 0.01 0.17 0.01 0.1 0.01 33
Investigational APIs AMG 517 Baicalein CFPPC Dipfluzine EGCG Lithium salicylate L-883555 NVX-144 Quercetin
0.022 0.017 0.0001 0.00027 23.6 33 0.0075 0.019 0.0026
Animal dose in literature PK studies‡
FDA-approved human dose*
CLogP§
BCS class
HD (mg)
D0
Species
HD (mg/kg)
HED (mg)
D0’
400 400 100 200 12 50 200 200 15 800 200 50
160 160 40 800 4 21 40 4.7 6 32 80 0.006
Dog Dog Dog Rat Dog Dog Dog Rat Rat Dog Dog Dog
20 11.2 10 20 0.4 2.5 2.5 10 10 21 20 8.8
667 373 333 194 13 83 83 97 97 700 667 293
267 149 133 774 4.4 35 33 2.3 39 28 267 0.036
2.38 4.37 3.53 3.93 3.92 4.18 6.05 2.38 2.29 2.15 0.94 3.10
II II II II II II II II II II IV I
Rat Rat Dog Rat Rat Rat Monkey Rat Rat
500 121 50 40 100 576 3 20 100
4839 1171 1667 387 968 5576 58 194 968
880 278 66666 5714 0.16 0.68 31 41 1472
4.63 3.00 4.18 5.93 1.49 NA -0.49 1.36 1.30
II II II II I I IV IV IV
*Highest human doses of immediate-release oral solid dosage formulations were obtained from the FDA Orange Book (updated in May 2013). z For calculation purpose, the body weights of rat, dog and human were assumed to be 0.25, 10 and 60 kg, respectively, unless otherwise specified in the study. When the range of animal body weights was provided in the study, the median was used for calculation. § CLogP values were estimated by the ChemDraw Ultra 8.0 program. The chemical structures used for estimation were the uncharged forms. The CLogP value for lithium salts could not be obtained, while lithium salts were treated as a highly permeable API. API: Active pharmaceutical ingredient; BCS: Biopharmaceutics classification system; CFPPC: 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide; CLogP: Calculated partition coefficient; D0: Dose number based on highest human dose; D0’: Equivalent dose number based on highest HED; EGCG: Epigallocatechin gallate; HD: Highest dose; HED: Human equivalent dose; NA: Not available; PK: Pharmacokinetic.
data, the fold changes of Cmax range from an approximately fourfold decrease to a 44-fold increase. Overall, 52% of entries with RCmax values are accompanied by a less than sixfold Cmax increase by cocrystallization. Interestingly, AUC and Cmax changes exhibited by a cocrystal might not be achieved by the physical mixture of the corresponding API and coformer [54,70]. Correlation between RAUC and RCmax can also be evaluated. Before data comparison, both dimensionless parameters were subjected to a natural logarithmic transformation, thereby enabling us to distribute the resulting LnRAUC and LnRCmax on a symmetric scale [71]. The logarithmic transformation also facilitates a qualitative analysis of relative PK and solubility data. For example, a positive value of LnRAUC corresponds to an AUC increase affected by cocrystallization, while a negative LnRAUC reflects a decrease in AUC. An LnRAUC of zero means that there is no effect of cocrystallization on AUC. A relatively strong linear correlation (R2 = 0.88) is observed in the plot of LnRAUC versus LnRCmax (Figure 3C). Quantitatively, relative AUC and Cmax changes 1262
by a cocrystal are comparable on the logarithmic scale, as evidenced by the slope of the regression line. Based on the strong correlation of this plot and the number of data points, it is reasonable to assert that correlation of RAUC and RCmax is a general artifact of cocrystallization. Since the ‘cocrystal effect’ upon bioavailability has often been attributed to changes in RSol, the potential AUC increase by cocrystallization was correlated to the aqueous solubility of the parent API. All 20 APIs with RAUC data are included in our analysis. For each parent API, the potential AUC increase by cocrystallization is represented by the maximal RAUC exhibited by its cocrystals (i.e., RAUCmax). In order to account for variation of dose strength, D0’ is used as a quantitative solubility measure for each parent API. After natural logarithmic transformation, D0’ and RAUCmax data were plotted (Figure 4). In general, a higher D0’ correlates to a greater value of RAUCmax, indicating that a higher RAUC value is generally associated with a parent API that exhibits relatively low solubility. Solubility increase by cocrystallization would be expected to have less impact
Expert Opin. Drug Metab. Toxicol. (2014) 10(9)
Impact of pharmaceutical cocrystals
API distribution
A.
B.
Entries with investigational APIs (BCS IV) 7.9%
Approved APIs (BCS I) 4.8%
Investigational APIs (BCS IV) 14.3%
Entries with approved APIs (BCS I) 3.9%
Entries with investigational APIs (BCS II) 31.6%
Investigational APIs (BCS II) 19.0%
Entries with approved APIs (BCS II) 48.7%
Approved APIs (BCS II) 47.6%
Investigational APIs (BCS I) 9.5%
Entries with investigational APIs (BCS I) 6.6%
Approved APIs (BCS IV) 4.8%
Entries with approved APIs (BCS IV) 1.3%
Figure 2. A. Statistics on BCS classification of parent APIs involved in literature cocrystal PK studies (n = 21). B. Statistics on cocrystal data entries categorized by the BCS classification of their corresponding parent APIs (n = 76). API: Active pharmaceutical ingredient; BCS: Biopharmaceutics classification system; PK: Pharmacokinetic.
A.
B. 20
10 AUC
15
AUC Count number
Count number
Cmax
10 5 0
1
≤
2 FI
