PERSPECTIVE pubs.acs.org/crystal
Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals Published as part of the Crystal Growth & Design 10th Anniversary Perspective N. Jagadeesh Babu† and Ashwini Nangia*,‡ †
Laboratory of Biophysics and Surface Analysis, School of Pharmacy, Boots Science Building, Room D09, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K. ‡ School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India ABSTRACT: The current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing R&D costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility is unsuccessful with molecules that lack ionizable functional groups, have sensitive moieties that are prone to decomposition/racemization, and/or are not sufficiently acidic/ basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the enhanced solubility profiles of cocrystals are analyzed. The peak dissolution for pharmaceutical cocrystals occurs in a short time ( 1.72 are categorized as high-permeability because metoprolol is known to be 95% absorbed from the GI tract. Since experimental human jejunal membrane permeability data are available for 29 reference drugs only, the correlation is based on estimated or calculated log P (or C log P) values. The agreement between the literature and calculated values was excellent. In silico permeability calculations demonstrated ∼75% accuracy in classifying r 2011 American Chemical Society
these 29 drugs with human permeability data and ∼90% accuracy for the 14/29 FDA reference drugs for permeability. High/low solubility is defined with reference to the Dose number, Do, which is the ratio of the highest drug dose strength in the administered volume (taken as 250 mL = a glass of water) to the saturation solubility of that drug in water (measured in mg/L). A Do value of 1 for low solubility compounds. In simple terms, Do is the number of glasses of water required to dissolve the tablet at its highest dose. Do values of 25100 are considered low solubility drugs and this number can even exceed 1000 (Figure 1). Apart from the dimensionless Do parameter, solubility classification for drugs in low, moderate, and high category3 is given in Table 1. The serious problem posed by low solubility drugs was highlighted in recent Chemical & Engineering News articles.4 Received: April 18, 2011 Revised: May 16, 2011 Published: May 18, 2011 2662
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Figure 1. The Biopharmaceutics Classification System of drugs (ref 1) according to intestinal absorption and oral administration parameters. The Do solubility scale is shown on top.
Table 1. Solubility Classification of Drugs with Dose of about 1 mg/kg (mg of drug/kg of body weight)a solubility (mg/L)
a
classification
comments
65
high
no solubility problem
Data are taken from ref 3.
Table 2. Low Solubility Drugs in the Market and in the Development Pipeline According to the Biopharmaceutics Classification Systema BCS class
a
% drugs
% drugs
solubility
permeability
on market
in R&D pipeline 510
I
high
high
35
II
low
high
30
6070
III
high
low
25
510
IV
low
low
10
1020
Data are taken from ref 4b.
Over 80% drugs are sold as tablets. About 40% of marketed drugs have low solubility. More alarming is double the percentage of drug candidates in the R&D pipeline (8090%) which could fail due to solubility problems (Table 2). A major cause for the current crisis in drug solubility may be traced to the High Throughput Combinatorial Medicinal Chemistry research programs popular in the 1990s.5 Thousands of new drug molecules were discovered and screened for biological activity using dimethyl sulfoxide (DMSO) and polyethyleneglycol (PEG) as solvents in robotic set ups. Whereas this rapid screening technology produced hundreds of molecules which bind strongly to drug targets, the use of DMSO and PEG as solvents resulted in those molecules having extremely low aqueous solubilities (μg/L range), often referred to as “brick dust” or “chalk powder” compounds. That “a drug’s behavior depends on much more than the molecular structure”4 has led to the emphasis shifting often in pharmaceutical R&Ds from MedChem to PharmDev (medicinal chemistry discovery to pharmaceutical form development). There is a heightened awareness that the solid drug form dictates properties such as stability, solubility, hygroscopicity, dissolution rate, and bioavailability in the past decade. Incidentally, this period coincides with the launch of
Figure 2. A cocrystal is a stoichiometric molecular complex of a molecule (blue) with a coformer (red) assembled via noncovalent interactions, predominantly hydrogen bonds. In a pharmaceutical cocrystal, the molecule is an API and the coformer is a GRAS compound. Crystallization of the API gives the reference drug form, whereas cocrystallization leads to multicomponent crystal structures (cocrystal).
Crystal Growth & Design journal in the year 2000. The 10th Anniversary of CG&D6 roughly coincides with an increasing focus on the development of novel solid drug forms as an important and innovative step in pharmaceutical R&D.7 Slowly but perceptibly New Form Discovery is the frontrunner solution to thicken the pipeline of new drugs compared to New Molecular Entities until about a decade ago. Topical reviews in CG&D,8 journals, and books9 highlight this paradigm shift toward pharmaceutical form discovery, selection, and optimization. The looming “patent cliffs” for several blockbuster drugs in the coming decade10 mean that new R&D strategies must be devised for the continued growth of the global pharmaceutical industry. The search for new pharmaceutical solids such as polymorphs, hydrates, solvates, cocrystals, salts, etc. by manual experimentation has become a highthroughput crystallization technology11 in the 21st Century. We present in this Perspective some recent examples of cocrystals that exhibit enhanced solubility compared to the reference drugs and compare their dissolution profiles with those of amorphous drugs. We are aware that even the definition of what is a cocrystal (or co-crystal)12 is not agreeable on a common platform,13 although there is some consensus on the meaning and usage of the word pharmaceutical cocrystal.14 We will use the word cocrystal to describe hydrogen-bonded molecular complexes schematized in Figure 2. When the molecule (blue) is an active pharmaceutical ingredient (API) and the coformer (red) is a molecule selected from the list of benign chemicals for human consumption (generally regarded as safe by the FDA or GRAS),15 the resulting crystalline adduct is a pharmaceutical cocrystal. Such molecular complexes or cocrystals (other names are molecular compounds, heteromolecular complexes, addition compounds) of drugs with partner molecules having complementary functional groups were reported by the Caira group16 in the mid 1990s, but they lay dormant for a few years. The popularity of cocrystals (a nomenclature that now supersedes earlier terminologies such as molecular compounds, molecular complexes, etc.) in the crystal engineering17 and pharmaceutical chemistry communities may be traced to the feature article by Almarsson and Zaworotko in 2004.14 Blagden et al.9a recently highlighted the use of hydrogen bonding (Etter)18 and crystal 2663
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Table 3. BCS Classification of a Few Drugs in the Market (Listed Alphabetically in Each Category)a Class I high solubility, high permeability
a
Class II low solubility, high permeability
diltiazem, metformin hydrochloride, metoprolol,
atovaquone, carbamazepine, danazol, felodipine,
paracetamol, propranolol, pseudoephedrine sulfate,
glibenclamide, griseofulvin, ketoconazole, mefenamic acid,
theophyline, verapamil
nicardipine, nifedipine, nisoldipine, troglitrazone
Class III high solubility, low permeability
Class IV low solubility, low permeability
acyclovir, alendronate, atenolol, captopril, cimetidine,
cefuroxime, chlorothiazine, cyclosporin, furosemide,
enalprilate, neomycin, ranitidine
itraconazole, tobramycin
Data taken from ref 25.
engineering (Desiraju)19 strategies to improve the solubility and dissolution profile of drugs. The literature discussed in this article is taken from papers published largely in the past decade.
’ SOLUBILITY OF PHARMACEUTICALS When a solute is placed in a solvent, mixing of solute and solvent molecules occurs due to randomization, that is, entropy of mixing is the driving factor. The second factor is enthalpy: intermolecular interactions and hydrogen bonds between the solute and solvent molecules are stronger compared to solute 3 3 3 solute and solvent 3 3 3 solvent interactions. The stronger solute 3 3 3 solvent hydrogen bonds favor dissolution of the solid for enthalpic reasons. The free energy of mixing (eq 1) will determine the possibility and extent of the solute and solvent mixing in solution. As is true for any thermodynamic process, mixing will occur spontaneously when ΔGmix is negative. ΔGmix ¼ ΔH mix TΔSmix
ð1Þ
where T is the temperature in Kelvin. The same equation is applicable to single and multicomponent drug forms such as [A], [B], [A: B], [Aþ B], etc. where A represents drug and B is the coformer or salt former as molecule, ion, etc. The gain in the enthalpy of hydration arising from hydrogen bonds made between water and the dissolving compound(s) more than compensates for the energy required to break the solid-state species. Because of charge-assisted hydrogen bonds and electrostatic interactions, the enthalpy of hydration for ionic salts is greater than that for neutral cocrystals. Hence, salts are more water-soluble and the preferred formulation for improving drug dissolution and solubility. The mixing of molecules begins at the surface and continues until saturation of the solution is reached. The number of molecules leaving the bulk solid into the solution and those reattaching becomes equal in a state of dynamic equilibrium. The amount of solute which dissolves in the solvent at the equilibrium state is the solubility of the substance. The rate at which this state is reached is the dissolution rate.20 Thus solubility is a thermodynamic parameter, while dissolution is a kinetic phenomenon. Both these factors are important for pharmaceutical solids because a drug will deliver its therapeutic effect only if a sufficient amount of the effective dose is absorbed fast enough in the stomach and gastrointestinal tract. The equilibrium method of solubility measurement is suited for those drugs that do not undergo transformation in the biological medium (which is aqueous and in the pH range 17) for a long enough time (between 24 and 48 h). The intrinsic dissolution rate (IDR) measurement overcomes the effects of crystal habit and particle size. The apparent solubility (Cm) refers to the concentration of
the drug at the apparent equilibrium or supersaturation. Apparent solubility is distinct from equilibrium solubility (Cs) which is reached at infinite time. For stable, crystalline drug forms, Cm has about the same value as Cs. The apparent solubility of a metastable drug form (Cm), be it anhydrate, polymorph, or cocrystal, is a calculated parameter and not measured directly like the equilibrium solubility (Cs). The dissolution rate is proportional to drug solubility provided that there are no phase transitions. For drugs that undergo phase change during the solubility experiment, the IDR of the drug must be measured (designated Jm and Js for metastable and stable polymorphs), and these values in turn are used to estimate the apparent solubility of the metastable species (eq 2).21 Equation 2 can be derived from the NoyesWhitneyNernst equation. The use of apparent solubility measurements are exemplified elsewhere.22 The disk intrinsic dissolution rate (DIDR)23 is yet another approach to determine the solubility class membership, suited to those drugs which undergo a phase transformation. DIDR is a rate phenomenon instead of an equilibrium quantity and hence likely to correlate more closely with in vivo drug dissolution dynamics than solubility. Cm ¼ Cs ðJ m =J s Þ
ð2Þ
In general, crystalline forms of drugs are the most stable (highest density and melting point) and consequently have the lowest free energy and solubility. Solvated forms (termed pseudopolymorphs) are the least soluble form in that solvent; that is, hydrates will generally be less soluble than anhydrate drugs in water. Because the hydrate form already has drug 3 3 3 water hydrogen bonds, the free energy released on further bonding with solvent water molecules is less than that for the anhydrate form. Consequently, drug hydrates are less soluble than their anhydrate.24 Amorphous drugs are the least stable. Such high entropy phases are prepared by arresting or freezing the molecules faster than they can organize in the crystalline lattice. Amorphous phases can exist as solids or even as supercooled glassy states. They lack the long-range order and periodicity characteristic of the crystalline state. The high free energy and low density of the amorphous phase mean that amorphous drugs dissolve faster than their crystalline forms. However, their metastable nature and transformation to the crystalline form during storage are serious concerns for drug developers. Apart from good oral absorption, the drug must be permeable through the GI membrane. BCS class I drugs have good solubility and good permeability. Some common examples of BCS class IIV drugs in the market25 are listed in Table 3. There are two well-practiced approaches in the prior art to improve drug solubility. (1) The formation of salts is the oldest and most popular method for improving the stability and 2664
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solubility of drug substances.26 (2) By amorphization, that is, the preparation of high energy metastable amorphous drug formulations of faster dissolution rates.27 A major driving force for the higher solubility of salts is the ionic and electrostatic interactions. Basic or acidic drug molecules are converted into salts by reaction with inorganic acids and bases. Charged counterions, such as Cl, PO43, Naþ, Ca2þ, etc. dramatically increase the ionic, polar, and hydrogen bonding interactions with solvent water molecules and in this way rapidly transport the ionized drug to the aqueous medium. The higher free energy of the amorphous phase, the random orientation of molecules, and the larger surface area due to smaller particle size increase the exposure of hydrophobic and hydrophilic functional groups leading to improved wettability for amorphous drugs. However, transformation of the metastable amorphous form to the stable crystalline phase during dissolution is a serious complication.28 A high glass transition temperature (Tg > 75 °C) minimizes accidental phase transition even though there are examples of drugs that undergo crystallization below Tg, promoted by water molecules and surface crystallization. Polymer additives such as polyvinylpyridone (PVP), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyethyleneglycol (PEG), etc. are used as stabilizers29 to increase the glass transition temperature of amorphous drugs. Apart for the above methods, there are several other drug delivery strategies such as micronization,
inclusion complexes with cyclodextrins and surfactants, nanoparticle vehicles, dispersion in different carriers, polymorphs, polyamorphs, supersaturating drug-delivery systems (SDDS), etc. described elsewhere.7,30
’ SOLUBILITY OF AMORPHOUS DRUGS The dissolution profile and solubility of amorphous forms of a few drugs compared to their crystalline phases are discussed below. Atorvastatin Calcium. The equilibrium solubility of crystalline atorvastatin calcium is only 140 μg/mL, whereas amorphous particles prepared by supercritical antisolvent process (SAS) have high apparent solubility of 460 μg/mL. However, the amorphous phase solubility decreases after 24 h to about 200 μg/mL.31 Their powder dissolution curves are displayed in Figure 3. The lack of long-range order in the amorphous phase and its higher Gibbs free energy resulted in rapid dissolution evidenced in the maximum supersaturated concentration after 10 min, which then decreased due to solvent-mediated transformation of amorphous to crystalline atorvastatin (Table 4). Even so, a higher concentration of atorvastatin for the amorphous form (300 μg/mL), more than twice than that for the crystalline phase, was maintained for up to 3 h. The intrinsic dissolution rates of amorphous atorvastatin showed peak plasma concentration at 1015 min, which then decreased over the next 56 h due to increase in the crystalline content (Figure 4). The amorphous form dissolution curves have slopes and peak values higher than those of the crystalline form, reaching the asymptotic equilibrium value at 8 h. The transient increase in IDR and apparent solubility of the amorphous drug were sufficient to deliver a 24 times higher oral dose in rats.
Figure 3. Powder dissolution profiles of unprocessed atorvastatin calcium particles (9), SAS processed amorphous atorvastatin calcium precipitated from acetone solution (b), SAS processed amorphous atorvastatin calcium precipitated from THF solution (2), spray-dried amorphous atorvastatin calcium from acetone solution (O), and spraydried amorphous atorvastatin calcium from THF solution (Δ) (n = 3, mean ( S.D.). Published with permission from ref 31. Copyright 2008 Elsevier.
Figure 4. Plasma concentrationtime curves of atorvastatin calcium. Symbols are the same as in Figure 3 (n = 5, mean ( S.D.). Published with permission from ref 31. Copyright 2008 Elsevier.
Table 4. Intrinsic Dissolution Rate and Solubility of Crystalline and Amorphous Atorvastatin Calcium in Water at 37 °Ca intrinsic dissolution rate μg/(min/cm2)
form
solubility μg/mL
mean particle size
142.2
3.83 ( 0.08 μm
crystalline
84.9
amorphous
early phase (10 min)
late phase
SASAb
288.5 ( 3.4)
179.5 ( 2.1)
483.2 ( 3.4)
68.7 ( 15.8 nm
SDAc
280.1 ( 3.3)
175.5 ( 2.1)
469.1 ( 3.3)
3.62 ( 0.15 μm
a
Increase in IDR and solubility compared to the crystalline form is given as ( times). Data are taken from ref 31. b SASA: supercritical antisolvent amorphous from acetone. c SDA: spray-dried amorphous from acetone. 2665
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Table 5. Interaction Radius of Intact and Ground Cefditoren Pivoxil with Watera
a
grinding time (min)
interaction radius with water (cal/cm3)1/2
0
11.4
1 3
12.0 8.2
5
6.4
10
5.3
20
4.2
30
5.9
Data are taken from ref 32.
Figure 5. Dissolution patterns of intact and ground cefditoren pivoxil in water at 37 °C. Grinding time: 0 min (9), 1 min (0), 3 min (2), 5 min (Δ), 10 min (b), 20 min (O), and 30 min ((). Published with permission from ref 32. Copyright 1999 Elsevier.
Figure 6. Relationship between crystallinity and concentration of cefditoren pivoxil at 20 min. Published with permission from ref 32. Copyright 1999 Elsevier.
Cefditoren Pivoxil. The decrease in crystalline content of cefditoren pivoxil due to grinding and its reduced particle size were correlated with the apparent solubility of the drug.32 Crystalline cefditoren pivoxil was ground in a mechanical ball mill and the change in amorphous content was monitored with time by X-ray powder diffraction. The characteristic “amorphous hump”, a broad and shallow peak centered at 2025° 2θ, was clear after 30 min of grinding. There was a decrease in particle size and interaction radius after a longer grinding time (Table 5). The dissolution curves in water showed a maximum concentration at about 20 min, and the curves are higher after longer grinding. Thus, the peak concentration correlates nicely with the extent of amorphouscrystalline drug content (Figures 5 and 6).
Figure 7. Dissolution profiles for HGAP nanosized CFA (9) and spray-dried CFA (b). Published with permission from ref 33. Copyright 2006 American Chemical Society.
Figure 8. Plasma concentration vs time profile after oral administration of unprocessed CFA (b), spray dried CFA (9), PPT-CFA (O), and sono-CFA (2) in rats. Published with permission from ref 34a. Copyright 2008 Elsevier.
Cefuroxime Axetil (CFA). CFA is a cephalosporin antibiotic (BCS class IV drug) possessing high activity against a wide spectrum of Gram-positive and Gram-negative microorganisms. The amorphous form of CFA has higher solubility and good stability. Amorphous CFA nanoparticles were prepared by the novel high-gravity antisolvent precipitation (HGAP) method to further improve the dissolution rate.33 CFA particles prepared by HGAP were spherical with a mean particle size of 305 nm, while commercial spray-dried CFA particles were hollow spheres with a mean particle size of 15 μm. The small particle size and large specific surface area of amorphous CFA nanoparticles resulted in a faster dissolution rate (Figure 7). At 37 °C, the dissolution rate of the nanosized CFA was increased to 78% after 30 min, while only 51% of the commercial spraydried CFA dissolved at that time. After 80 min, all of the nanosized CFA particles had completely dissolved, but there was still 40% of spray-dried CFA undissolved. In another article,34 it was reported that the plasma concentration for SONOCFA (prepared by sonoprecipitation) exhibited significant improvement in drug absorption than the spray-dried PPT-CFA (precipitation without sonication) or unprocessed CFA (crystalline) (Figure 8). Both the Cmax and AUC024h values of SONOCFA were approximately 1.5 fold better than those of the spray-dried CFA and 2-fold greater than crystalline CFA, indicating a remarkable improvement in the oral absorption of CFA when administered in the form of amorphous nanoparticles. PPT-CFA also showed improvement in 2666
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Figure 9. Experimental aqueous solubility of amorphous and crystalline indomethacin at 25 °C (b amorphous, 9 γ-crystal). Published with the permission from ref 35a. Copyright 2000 Plenum Publishing.
PERSPECTIVE
Figure 11. Dissolution profile of wet milled itraconazole (ITZ) colloidal dispersion and URF-ITZ colloidal dispersion (ultra rapid freeze) in simulated lung fluid (pH 7.4) at supersaturation conditions (100 times the equilibrium solubility of micronized crystalline ITZ was added) in a USP Dissolution Tester at 100 rpm and 37 °C. Published with permission from ref 37. Copyright 2010 Elsevier.
Figure 12. Plasma concentration of ITZ in rats after a single-dose inhalation of nebulized ITZ which was wet-milled or URF colloidal dispersion. Published with permission from ref 37. Copyright 2010 Elsevier.
Figure 10. Dissolution of γ indomethacin and amorphous indomethacin prepared by melt quenching and cryogrinding at 7 mL/min flow rate in the dissolution cell: melt quenched (9), melt quenched cryoground (b), 1 h cryoground ((), 3 h cryoground (), and γ crystalline (2). (a) Cumulative amount vs time, and (b) dissolution rate vs time. Published with permission from ref 36. Copyright 2010 American Chemical Society.
Cmax and Tmax over unprocessed and spray-dried CFA owing to the amorphous and porous nature of particles. Indomethacin. The solubility of amorphous indomethacin is greater than that of the crystalline γ form over a wide temperature range of 545 °C. The peak solubility always occurred in the first 1015 min of the experiment, and this value is at least two times higher than the steady-state solubility35 (Figure 9) at the end of experiment (2 h). There was partial conversion of the metastable amorphous phase to the crystalline form(s) by supersaturation of the dissolution medium during the solubility run. Although in vitro to in vivo kinetic measurements and transformation rates are not known, it is expected that the solubility
advantage of the amorphous form will be realized in animal and human trials. In a related paper,36 amorphous indomethacin was prepared by melt quenching and cryogrinding and the improved dissolution rates were compared with γ indomethacin (Figure 10) in a flow cell. The phase transformation from amorphous to the γ phase in water was monitored by in situ Raman microscopy. Itraconazole. It is known that drug particles in the 100 nm size dissolve much faster than micronized particles (about micrometer -sized particles). The potential for increased surface area and electrostatic interactions between ultrafine particles and the aqueous medium can dramatically improve bioavailability. Itraconazole (ITZ) is a highly insoluble drug (ng/mL solubility in water). The effect of crystalline vs amorphous nanoparticles on drug bioavailability was compared. The nanocrystalline drug was prepared by wet milling and the amorphous nanostructured aggregates by ultrarapid freeze process (URF).37 There was 36 fold improvement in the Cmax concentration which peaks quite early in the concentration vs time profile (Figures 11 and 12). Interestingly, the dissolution profiles match very nicely with the concentration of ITZ in plasma (good in vitro in vivo 2667
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correlation). Some salient pharmacokinetic parameters are compared in Table 6. Solubility Trends. The ratio of solubility between amorphous to crystalline polymorphs of the same drug (414) is much higher than those between crystalline polymorphs (23 times).38 The calculated solubility ratio is even higher (101600, see Table 7), but such predictions are not reliable because of amorphous-to-crystalline transformation during the dissolution/bioavailability experiments. Some well-known examples of amorphous: crystalline solubility advantage are nifedipine (∼6),39 ritonavir, a class IV drug (∼10),40 and tolbutamide (46).41
’ DISSOLUTION PROFILE OF PHARMACEUTICAL COCRYSTALS After discussing the solubility advantage of a few amorphous drugs (in native state or stabilized in a polymer matrix) over the crystalline modification, a few examples from the cocrystal category are illustrated. Even though sporadic examples of drug cocrystals were reported in the 1990s16 and perhaps even earlier,13d a systematic effort to rationally modify the physicochemical properties of drugs via cocrystal engineering is of recent times, notably in the past decade. Cocrystals offer several benefits over traditional salts. (1) Drug molecules which lack easily ionizable functional groups (such as those containing carboxamide, phenol, weakly basic N-heterocycles, etc.) can be intermolecularly manipulated via cocrystals to tune their physicochemical properties. (2) A practical advantage is that the number of neutral GRAS coformers15 far exceeds the number of available counterions for making pharmaceutical salts.26 (3) Since drug molecules advancing past MedChem discovery laboratories are becoming more complex and highly functionalized, there is a need to develop novel methods for solubility improvement under mild and neutral crystallization conditions rather than the extreme pH regimes of salt titration. The last reason is equally applicable to chiral drugs which may undergo racemization during salt formation. The following examples demonstrate that pharmaceutical cocrystals offer a viable platform to improve the solubility of BCS class II and IV drugs.
DigoxinHydroquinone. One of the earliest examples of solubility/dissolution advantage in a drug complex is the digoxin hydroquinone molecular complex reported by Higuchi and Ikeda in 1974.42 The authors estimated a 1:1.5 stoichiometry for the complex based on the concentration of hydroquinone in solution. Even though the word cocrystal is not strictly applicable here because the exact stoichiometry of drug to coformer was not established, the increase in bioavailability of the cocrystal compared to the drug (Figure 13) is notable. The concluding line of this historical paper,43 “The principle of complexing a drug with substances such as hydroquinone to enhance dissolution might be applied to other medications whose adsorption is erratic following poor in vivo dissolution,” was a very early forecast of the now mature field of pharmaceutical cocrystals over 30 years later. AMG517 Cocrystals. AMG517 is a development lead candidate of Amgen for the treatment of chronic pain. The ether linkage flanked by pyrimidine and benzathiazole moieties makes the structure sensitive to degradation in the strongly acidic pH conditions of salt formation. The structures of about a dozen cocrystals of AMG517 with carboxylic acids and carboxamides were determined by single crystal X-ray diffraction, the cocrystals were characterized using differential scanning calorimetry, thermal gravimetry analysis, powder X-ray diffraction (DSC, TGA, PXRD), and their solubility/stability were determined. Solubilities were measured in a slurry (3.33 mg/mL) under fasted simulated intestinal fluid conditions (FaSIF, pH 6.8, small intestine conditions).44 Solubilities could not be measured at 0.01 N HCl (pH 2, stomach conditions)44,45 because they were
Table 6. Plasma ITZ Concentration in Rats after a Single Dose Inhalation of Nebulized Aerosol Itraconazolea pharmacokinetic parameters
a
wet-milled ITZ
URF-ITZ
Cmax (ng/mL) Tmax (h)
50 2.7
180 4.0
AUC024 (ng h/mL)
662
2543
Data taken from ref 37.
Figure 13. Dissolution rate profiles obtained for the digoxin hydroquinone complex and free digoxin under comparable dissolution conditions. Published with permission from ref 42. Copyright 1974 Wiley.
Table 7. Predicted and Experimental Solubility Ratio for Amorphous to Crystalline Drug Forms.a drug
a
forms
calculated solubility ratio
experimental solubility ratio
temperature (°C)
4.5
medium
indomethacin
amorphous/ γ-crystal
15 40
25
water
glibenclamide
amorphous/crystal
100 1600
14
23
buffer
glucose
amorphous/crystal
15 50
21
20
ethanol
griseofulvin
amorphous/crystal
40 440
1.4
21
water
hydrochlorothiazide iopanoic acid
amorphous/crystal amorphous/I-crystal
20 110 12 20
1.1 3.7
37 37
HCl and PVP buffer
polythiazide
amorphous/crystal
50 450
9.8
37
HCl and PVP
Data taken from ref 35a. 2668
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Figure 14. (a) Structure of AMG517. (b) Solubility of AMG517 and its five cocrystals with carboxylic acids. The cocrystals show spring and parachute (benzoic, hexanoic) or spring only (lactic) profile. The pure drug has peak solubility of 5 μg/mL. The profiles are similar for the other carboxylic acid and carboxamide cocrystals studied (c and d). All measurements were carried out on 3.33 mg/mL concentration slurry in fasted simulated intestinal fluid (pH 6.8). Published with permission from ref 44. Copyright 2008 and 2009 American Chemical Society.
generally lower under acidic conditions and due to instability of the drug at low pH. The crystal structures confirmed that the product is a neutral cocrystal and not an ionic salt; that is, the COOH is hydrogen bonded to the thiazole N and the NH donor is bonded to the CdO in a neutral motif. The Smax of benzoic acid cocrystal (21 μg/mL) is about 10 times higher than that of the pure drug (2 μg/mL) in FaSIF conditions (Figure 14). Although there was conversion of the cocrystal to the drug hydrate at the end of the solubility experiment (24 h), the transient advantage in improved solubility (during 13 h) is high enough to give increased drug exposure in pharmacokinetic studies. Most of the drug cocrystals were found to be stable after 1 month at 40 °C/ 75% RH conditions; they were not hygroscopic and there was no perceptible change in their PXRD line pattern. A control experiment on the AMG517sorbic acid cocrystal45 showed that the solubility advantage is lost as the cocrystal disintegrates to the drug and the coformer. The Smax of 29 μg/mL at 1.1 h for the cocrystal declined rapidly to reach the drug solubility value of 4 μg/mL at 2.5 h (Figure 15), and after that point the free base solubility operated. These dissolution rate curves suggest that the enhanced apparent solubility will apply in the upper GI tract for drug absorption. Carbamazepine Cocrystals. Carbamazepine, an important antiepileptic agent, exists in four polymorphic forms. This waterinsoluble drug with a high dose (>100 mg/day) is the archetype for evaluating solubility improvement in cocrystals. The carbamazepine nicotinamide (CBZNCT) crystal structure is sustained by the carboxamide homosynthon between drug molecules which are
Figure 15. Solubility of AMG517 free base, sorbic acid cocrystal, and coformer. Smax occurs at 1.1 h and the equilibrium value is reached at 2.5 h. Published with permission from ref 45. Copyright 2008 WileyInterscience.
flanked on both sides by NCT coformers via mutual NH 3 3 3 O hydrogen bonds. The solubilities of CBZ, NCT, and CBZNCT were determined in absolute ethanol at set temperatures between 25 and 60 °C.46 The equilibrium was taken to have been reached when a few crystals remained in suspension. The final form was confirmed by X-ray powder diffraction or visual microscopy of the solid residue. The solubility curves are shown in Figure 16. The concentration of CBZ and NCT in equilibrium with the cocrystal is related by eq 3. K sp ¼ ½CBZ½NCT
ð3Þ
The solubility product was calculated by dissolving the cocrystal in EtOH at 25 °C (Ksp = 0.0125 (mol/L)2). The inverse 2669
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PERSPECTIVE
relationship of CBZNCT cocrystal solubility with increasing NCT concentration is clear in Figure 16a. The solubility of pure CBZ is invariant to the NCT amount in solution. In the expanded view diagram (Figure 16b), the concentration of both CBZ and NCT decrease as the cocrystal grows with consumption of both components. The phase diagram is divided into four regions: (I) undersaturated clear solution; (II) solution in equilibrium with CBZ crystals; (III) point A in equilibrium with both CBZ and
Figure 16. Phase diagram of CBZNCT system. Solid lines are CBZ (horizontal) and NCT (vertical) solubility curves, dashed lines are CBZNCT cocrystal solubility curves, solid square symbols are measurement points, solid red circle is the point A corresponding to the intersection of CBZ and CBZNCT solubility curves at 25 °C, and solid diamond symbols are the initial operating conditions. (a) Broad view of the phase diagram at different temperatures including NCT solubility curve, and (b) restricted view of the phase diagram with only CBZ and CBZNCT saturated curves at 25 °C, and location of the experiments. Published with permission from ref 46. Copyright 2009 Elsevier.
CBZNCT; and (IV) solution in equilibrium with cocrystals. No crystalline phase can develop in domain I. In domain IIa only CBZ can nucleate whereas in IIb both CBZ and CBZNCT can nucleate (supersaturated for both species), but the cocrystal is the metastable phase whereas the drug is stable. Both drug and cocrystal can nucleate in this zone. In IVa region, both drug and cocrystal can nucleate, but the relative stabilities are reversed with respect to zone IIa cocrystal is stable whereas the drug is metastable. In zone IVb, the solution is undersaturated in CBZ but supersaturated in CBZNCT cocrystal; here only cocrystal will nucleate. Since the solubility of NCT is high, the coformer is undersaturated in this region of the phase diagram and it will never nucleate at the concentrations considered. The results of slurry crystallization experiments monitored by a video camera, SEM images, and powder XRD are summarized in Table 8. The combined data suggest that CBZNCT cocrystals grow on the crystal faces of CBZ. The lower induction time for the cocrystal to appear when the solution is supersaturated in CBZ (run 2 vs run 1) indicates a heteronucleation mechanism for CBZNCT crystal nucleation. The phase diagram for CBZ and NCT constructed in EtOH show the importance of initial conditions of crystallization on the final outcome. Although the thermodynamic product is reached in the end, kinetic aspects are important in the experiment design. A 1:1 cocrystal of carbamazepinesaccharin (CBZSAC) was crystallized from alcoholic solvents. The cocrystal showed a dependence of dissolution rate on particle size: particles 80% dissolved after 60 min, whereas larger crystals >500 μm (up to 1 mm diameter) were 1000 μm, 5001000 μm, O 300500 μm, 2 150300 μm, 0 53150 μm, (
