Mechanisms by which moisture generates cocrystals

The purpose of this study is to determine the mechanisms by which moisture can generate cocrystals when solid particles of cocrystal reactants are exposed to deliquescent conditions (when moisture sorption forms an aqueous solution). It is based on the hypothesis that cocrystallization behavior during water uptake can be derived from solution chemistry using models that describe cocrystal solubility and reaction crystallization of molecular complexes. Cocrystal systems were selected with active pharmaceutical ingredients (APIs) that form hydrates and include carbamazepine, caffeine, and theophylline. Moisture uptake and crystallization behavior were studied by gravimetric vapor sorption, X-ray powder diffraction, and on-line Raman spectroscopy. Results indicate that moisture uptake generates cocrystals of carbamazepine-nicotinamide, carbamazepine-saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with cocrystal reactants deliquesce. Microscopy studies revealed that the transformation mechanism to cocrystal involves (1) moisture uptake, (2) dissolution of reactants, and (3) cocrystal nucleation and growth. Studies of solid blends of reactants in a macro scale show that the rate and extent of cocrystal formation are a function of relative humidity, moisture uptake, deliquescent material, and dissolution rates of reactants. It is shown that the interplay between moisture uptake and dissolution determines the liquid phase composition, supersaturation, and cocrystal formation rates. Differences in the behavior of deliquescent additives (sucrose and fructose) are associated with moisture uptake and composition of the deliquesced solution. Our results show that deliquescence can transform API to cocrystal or reverse the reaction given the right conditions. Key indicators of cocrystal formation and stability are (1) moisture uptake, (2) cocrystal aqueous solubility, (3) solubility and dissolution of cocrystal reactants, and (4) transition concentration.     

Reaction crystallization of pharmaceutical molecular complexes

A mechanism for cocrystal synthesis is reported whereby nucleation and growth of cocrystals are directed by the effect of the cocrystal components on reducing the solubility of the molecular complex to be crystallized. The carbamazepine:nicotinamide cocrystal (CBZ:NCT) was chosen as a model system to study the reaction cocrystallization pathways and kinetics in aqueous and organic solvents. Fiber optic Raman spectroscopy and Raman microscopy were used for in situ monitoring of the cocrystallization in macroscopic and microscopic scales in solutions, suspensions, slurries, and wet solid phases of cocrystal components. This study demonstrates the advantages of reaction cocrystallization methods to develop rational approaches for high-throughput screening of cocrystals that can be transferable to control batch and continuous cocrystallization processes.     

Indomethacin–Saccharin Cocrystal: Design,Synthesis and Preliminary Pharmaceutical Characterization

Purpose To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate. Materials and Methods Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin–saccharin cocrystal (hereafter IND–SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND–SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin. Results The IND–SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND–SAC cocrystal is unique vis-à-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND–SAC cocrystal system was considerably faster than that of the stable indomethacin γ-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND–SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods. Conclusions The IND–SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N−H⋯O hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (γ-form). Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Sulfa drugs as model cocrystal formers

A review of several aspects of cocrystallization involving sulfonamide drugs is presented, with a focus on other drug molecules as cocrystallization partners. Some earlier exploratory studies outlined here led to more recent systematic investigation of processes such as cocrystal preparation by solid-state cogrinding of individual components, selective cocrystal formation in competition experiments, and exchange reactions. These are discussed with reference to the drug sulfadimidine, which featured prominently as a model cocrystal former. Apart from their potential as medicinal agents, cocrystals and salts of sulfa drugs frequently display multiple related physicochemical phenomena including polymorphism, crystal isostructurality, and solvate formation, justifying past and current interest in their solid-state chemistry.     

An Investigation of Indomethacin–Nicotinamide Cocrystal Formation Induced by Thermal Stress in the Solid or Liquid State

The impact of thermal stress on indomethacin (IMC)–nicotinamide (NIC) cocrystal formation with or without neat cogrinding was investigated using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) microspectroscopy, and simultaneous DSC–FTIR microspectroscopy in the solid or liquid state. Different evaporation methods for preparing IMC–NIC cocrystals were also compared. The results indicated that even after cogrinding for 40 min, the FTIR spectra for all IMC–NIC ground mixtures were superimposable on the FTIR spectra of IMC and NIC components, suggesting there was no cocrystal formation between IMC and NIC after cogrinding. However, these IMC–NIC ground mixtures appear to easily undergo cocrystal formation after the application of DSC determination. Under thermal stress induced by DSC, the amount of cocrystal formation increased with increasing cogrinding time. Moreover, simultaneous DSC–FTIR microspectroscopy was a useful one-step technique to induce and clarify the thermal-induced stepwise mechanism of IMC–NIC cocrystal formation from the ground mixture in real time. Different solvent evaporation rates induced by thermal stress significantly influenced IMC–NIC cocrystal formation in the liquid state. In particular, microwave heating may promote IMC–NIC cocrystal formation in a short time. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2386–2395, 2014     

Physical stability enhancement of theophylline via cocrystallization

The crystal form adopted by the respiratory drug theophylline was modified using a crystal engineering strategy in order to search for a solid material with improved physical stability. Cocrystals, also referred to as crystalline molecular complexes, were prepared with theophylline and one of several dicarboxylic acids. Four cocrystals of theophylline are reported, one each with oxalic, malonic, maleic and glutaric acids. Crystal structures were obtained for each cocrystal material, allowing an examination of the hydrogen bonding and crystal packing features. The cocrystal design scheme was partly based upon a series of recently reported cocrystals of the molecular analogue, caffeine, and comparisons in packing features are drawn between the two cocrystal series. The theophylline cocrystals were subjected to relative humidity challenges in order to assess their stability in relation to crystalline theophylline anhydrate and the equivalent caffeine cocrystals. None of the cocrystals in this study converted into a hydrated cocrystal upon storage at high relative humidity. Furthermore, the theophylline:oxalic acid cocrystal demonstrated superior humidity stability to theophylline anhydrate under the conditions examined, while the other cocrystals appeared to offer comparable stability to that of theophylline anhydrate. The results demonstrate the feasibility of pharmaceutical cocrystal design based upon the crystallization preferences of a molecular analogue, and furthermore show that avoidance of hydrate formation and improvement in physical stability is possible via pharmaceutical cocrystallization.     

Formation mechanism of a new carbamazepine/malonic acid cocrystal polymorph

A new 2/1 carbamazepine (CBZ)/malonic acid (MA) cocrystal polymorph form C was formed using a vibrational rod mill, whereas the known cocrystal polymorph form A was prepared using a ball mill. IR measurements showed that the interaction between CBZ and MA in cocrystal form C was formed by amide-carboxylic acid heterosynthons, similar to that in cocrystal form A. However, NMR results showed that the molecular states of CBZ at the dibenzazepine ring appeared to be different, which could be due to variation in either the conjugation of the aromatic rings or the π-π interaction of CBZ. Factors affecting the formation of cocrystal polymorphs, such as heat and force, were investigated to clarify the formation mechanism.     

Matrix-Assisted Cocrystallization (MAC) Simultaneous Production and Formulation of Pharmaceutical Cocrystals by Hot-Melt Extrusion

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus® were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (∼five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2904–2910, 2014     

Following the surface response of caffeine cocrystals to controlled humidity storage by atomic force microscopy

Active pharmaceutical ingredient (API) stability in solid state tablet formulation is frequently a function of the relative humidity (RH) environment in which the drug is stored. Caffeine is one such problematic API. Previously reported caffeine cocrystals, however, were found to offer increased resistance to caffeine hydrate formation. Here we report on the use of atomic force microscopy (AFM) to image the surface of two caffeine cocrystal systems to look for differences between the surface and bulk response of the cocrystal to storage in controlled humidity environments. Bulk responses have previously been assessed by powder X-ray diffraction. With AFM, pinning sites were identified at step edges on caffeine/oxalic acid, with these sites leading to non-uniform step movement on going from ambient to 0% RH. At RH >75%, areas of fresh crystal growth were seen on the cocrystal surface. In the case of caffeine/malonic acid the cocrystals were observed to absorb water anisotropically after storage at 75% RH for 2 days, affecting the surface topography of the cocrystal. These results show that AFM expands on the data gathered by bulk analytical techniques, such as powder X-ray diffraction, by providing localised surface information. This surface information may be important for better predicting API stability in isolation and at a solid state API–excipient interface.     

Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin

The aim of present research was to investigate the physicochemical, mechanical properties, and stability characteristics of cocrystal of carbamazepine (CBZ) using saccharin (SAC) as a coformer. The cocrystals were prepared by solubility method and characterized by pH-solubility profile, intrinsic dissolution by static disk method, and surface morphology by scanning electron microscopy (SEM), crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and mechanical properties by Heckel analysis. Stability of the cocrystals were assessed by storing them at 60 (°)C for two weeks, 25 (°)C/60%RH, 40 (°)C/75%RH and 40 (°)C/94%RH for one month and compared with the stability of CBZ. The solubility profile of cocrystal was similar to CBZ. The cocrystal and CBZ have shown the same stability profile at all the conditions of studies except at 40 (°)C/94%RH. Unlike the CBZ, cocrystal was stable against dihydrate transformation. The compacts of cocrystal have a greater tensile strength and more compressibility. The Heckel analysis suggested that plastic deformation started at low compression pressure in the cocrystal than CBZ. In summary, the cocrystal form of carbamazepine provides another avenue for product development which is more stable than the parent drug.     

A Novel Drug-Drug Cocrystal of Levofloxacin and Metacetamol: Reduced Hygroscopicity and Improved Photostability of Levofloxacin

Levofloxacin (LVFX), a broad-spectrum antibacterial agent from the fluoroquinolone family, is universally prescribed with antipyretics, including paracetamol (APAP) analogs. In this study, a new drug-drug cocrystal of LVFX and an APAP analog was developed using a grinding and heating approach. Among 9 APAP analogs, only metacetamol (AMAP) was able to form a cocrystal with LVFX, with a stoichiometric ratio of 1:1. This cocrystal was obtained from a eutectic melt of anhydrous LVFX and AMAP after complete desorption of water from LVFX hemihydrate. The crystal structure of the cocrystal was determined by single-crystal X-ray structural analysis. Unlike LVFX hydrates, the LVFX-AMAP cocrystal did not form a channel structure where water molecules reside in LVFX hydrates. Thus, the LVFX-AMAP cocrystal did not undergo hydration under high relative humidity conditions during vapor sorption-desorption analysis and physical stability tests. LVFX photostability was improved by cocrystallization when compared with that of the hemihydrate because of hydrogen bond formation between the hydroxyl group of AMAP and the N-methylpiperazine group of LVFX, which is possibly involved in LVFX photodegradation. The LVFX-AMAP cocrystal, which is superior to LVFX hydrates in both pharmacological and physicochemical properties, is expected to be a useful solid form.     

Unintended water mediated cocrystal formation in carbamazepine and aspirin tablets

The water of crystallization released during dehydration of dibasic calcium phosphate dihydrate (DCPD) mediated the cocrystal formation between carbamazepine (CBZ) and nicotinamide (NMA) in intact tablets. The dehydration of DCPD, the disappearance of the reactants (CBZ and NMA) and the appearance of the product (CBZ-NMA cocrystal) were simultaneously monitored by quantitative powder X-ray diffractometry. In a second model system, the water of crystallization released by the dehydration of DCPD caused the chemical decomposition of aspirin. Salicylic acid, one of the decomposition products, reacted with CBZ to form CBZ-salicylic acid cocrystal in tablets. This is the first report of cocrystal formation in intact tablets, demonstrating water mediated noncovalent synthesis in a multicomponent matrix. While the potential implications of such transformations, on both the mechanical and biopharmaceutical properties, can be profound, their characterization, using conventional solution based analytical techniques, can be challenging.     

Inhibiting Sublimation of Thymol by Cocrystallization

A thymol:4,4’-dipyridyl (2:1) cocrystal (Form I) is reported to suppress thymol sublimation. The cocrystal was prepared via solution-mediated phase transformation and its structure is sustained by O-H (phenol) ··· N (pyridyl) hydrogen bonds between two individual components. A cocrystal polymorph (Form II) was formed via solid state transformation or via vapor phase upon heating. Using gravimetry analysis, it was demonstrated that cocrystal Form I decreased the sublimation rate of thymol by 38-fold. This study demonstrates that cocrystallization is an effective approach to reduce vapor pressure and sublimation of solids, thus achieving odor-masking.     

Kinetics Study of Cocrystal Formation Between Indomethacin and Saccharin Using High-Shear Granulation With In Situ Raman Spectroscopy

Pharmaceutical manufacturing processes are necessary to make solid dosage form even in cocrystal formation. In an effort to reduce the number of unit operations, high-shear wet granulation with cocrystallization system was proposed. In the present study, indomethacin-saccharin was chosen as a model compound, and the cocrystal formation kinetics was investigated during the consistent process. The role of each initial indomethacin crystal state (γ-form, α-form, or amorphous) for the kinetics was explored using in situ Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis as a chemometrics. Obtained granules were characterized by X-ray diffraction and tablet dissolution testing. The Raman peaks assigned to indomethacin-saccharin cocrystal were increased with granulation when ethanol was used as a binding solvent. In addition, the reaction kinetics of run samples which had different indomethacin forms was distinguished by best fitting using Avrami–Erofeev or Ginstling–Brounshtein model. The kinetic variance depended on the initial thermodynamic state of indomethacin because they had a different crystallization mechanism for the cocrystal. The scalable and feasible granulation method is required in the pharmaceutical industry.     

Dissolution Improvement and the Mechanism of the Improvement from Cocrystallization of Poorly Water-soluble Compounds

Purpose  To demonstrate improvement in the dissolution of exemestane and megestrol acetate from cocrystallization using various particle sizes and to investigate the mechanism of the improved dissolution. Methods  Cocrystal screening was performed by slurry crystallization. The cocrystals were identified and characterized by powder X-ray diffraction, thermal analysis, and single crystal X-ray diffraction. Different particle sizes of each cocrystal were prepared from organic solutions. Solubility and dissolution rates were evaluated using dissolution tests. Transformation behavior of the cocrystals in suspension was analyzed by PXRD and polarization microscopy. Results  Two novel cocrystals were obtained: exemestane (EX)/maleic acid (MAL) (cocrystal 1) and megestrol acetate (MA)/saccharin (SA) (cocrystal 2). Cocrystal 1 showed a high dissolution rate even with large particles. Cocrystal 2 showed supersaturation with fine particles. The transformation from cocrystal 1 to EX was observed within 1 min in suspension. Cocrystal 2 was transformed to MA within 2–4 h. Conclusions  Cocrystallizations of EX and MA improved initial dissolution rates compared to the respective original crystals. The mechanism of dissolution enhancement varied. With cocrystal 1, fine particle formation resulted in enhancement, whereas with cocrystal 2, enhancement was due to the maintenance of the cocrystal form and rapid dissolution before transformation to the original crystal. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding

The formation of cocrystal hydrates represents a potential route to achieve molecular materials with improved properties, particularly stability under conditions of high relative humidity. We describe the use of neat and liquid-assisted grinding for screening for hydrated forms of pharmaceutical cocrystals. In the case of liquid-assisted grinding, water is present in the reaction mixture as a liquid, whereas in the case of neat grinding, it is introduced by employing crystalline hydrates as reactants. The ability to form a cocrystal hydrate by either of the two methods appears to be variable, depending on the choice of cocrystal components. Theophylline readily forms a cocrystal hydrate with citric acid. This contrasts with the behavior of caffeine, which provides only an anhydrous cocrystal ("caffeine citrate") even when both reactants are crystalline hydrates. The preference of theophylline to form a cocrystal hydrate is qualitatively explained by similarity between crystal structures of the products and reactant hydrates. Overall, liquid-assisted grinding is less sensitive to the form of the reactant (i.e., hydrate or anhydrate) than neat grinding. For that reason liquid-assisted grinding appears to be a more efficient method of screening for cocrystal hydrates, and it is also applicable to screening for hydrates of APIs.     

Cocrystallization and amorphization induced by drug-excipient interaction improves the physical properties of acyclovir

Although acyclovir is one of the most important antiviral drugs used today, there are several problems with its physical properties. The aim of this study is to prepare cocrystals or amorphous complex of acyclovir using drug-excipient interactions to improve the physical properties of the drug, especially its dissolution rate and transdermal absorption. Screening for formation of cocrystals and the presence of amorphous acyclovir was conducted with various pharmaceutical excipinents, with the use of the solution-crystallization method and liquid-assisted cogrinding. The potential cocrystalline phase and the amorphized complex were characterized by PXRD, TG/DTA, IR, DSC and HPLC techniques. The screening indicated that acyclovir formed novel cocrystals with tartaric acid and was amorphized with citric acid. The acyclovir-tartaric acid cocrystal (ACV-TA cocrystal) structure was determined from synchrotron X-ray powder diffraction data. T(g) of the amorphous acyclovir-citric acid compound (ACV-CA amorphous) was determined by DSC. The initial dissolution rate of the ACV-TA cocrystals was considerably faster than that of anhydrous acyclovir. In vitro skin permeation of ACV-CA amorphous from polyethylene glycol (PEG) ointment was remarkably higher than that of the crystalline acyclovir. We successfully improved the physical properties of acyclovir by the cocrystallization and amorphization techniques, using pharmaceutical excipients.     

Monitoring ibuprofen-nicotinamide cocrystal formation during solvent free continuous cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool

The purpose of this work was to explore NIR spectroscopy as a PAT tool to monitor the formation of ibuprofen and nicotinamide cocrystals during extrusion based solvent free continuous cocrystallization (SFCC). Drug and co-former were gravimetrically fed into a heated co-rotating twin screw extruder to form cocrystals. Real-time process monitoring was performed using a high temperature NIR probe in the extruder die to assess cocrystal content and subsequently compared to off-line powder X-ray diffraction measurements. The effect of processing variables, such as temperature and mixing intensity, on the extent of cocrystal formation was investigated. NIR spectroscopy was sensitive to cocrystal formation with the appearance of new peaks and peak shifts, particularly in the 4800-5200 cm(-1) wave-number region. PXRD confirmed an increased conversion of the mixture into cocrystal with increase in barrel temperature and screw mixing intensity. A decrease in screw rotation speed also provided improved cocrystal yield due to the material experiencing longer residence times within the process. A partial least squares analysis in this region of NIR spectrum correlated well with PXRD data, providing a best fit with cocrystal conversion when a limited range of process conditions were considered, for example a single set temperature. The study suggests that NIR spectroscopy could be used to monitor cocrystal purity on an industrial scale using this continuous, solvent-free process.     

In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviour

Cocrystals have shown huge potential to improve the dissolution rate and absorption of a poorly water soluble drug. However, solution mediated phase transformation of cocrystals could greatly reduce the enhancement of its apparent solubility and dissolution rate. The aim of this study is to gain a deep understanding of the phase transition behaviour of cocrystals during dissolution and to investigate the improvement of dissolution rate. Dissolution and transformation behaviour of carbamazepine–nicotinamide (CBZ–NIC) cocrystal, physical mixture and different forms of carbamazepine: form I (CBZ I), form III (CBZ III) and dihydrate (CBZ DH) were studied by different in situ techniques of UV imaging and Raman spectroscopy. It has been found that compared with CBZ III and I, the rate of intrinsic dissolution rate (IDR) of CBZ–NIC cocrystal decreases slowly during dissolution, indicating the rate of crystallisation of CBZ DH from the solution is slow. In situ solid-state characterisation has shown the evolution of conversion of CBZ–NIC cocrystal and polymorphs to its dihydrate form. The study has shown that in situ UV imaging and Raman spectroscopy with a complementary technique of SEM can provide an in depth understanding during dissolution of cocrystals.     

Investigation of the Effect of Hydroxypropyl Methylcellulose on the Phase Transformation and Release Profiles of Carbamazepine-Nicotinamide Cocrystal

Purpose

The aim of this work was to investigate the influence of hydroxypropyl methylcellulose (HPMC) on the phase transformation and release profile of carbamazepine-nicotinamide (CBZ-NIC) cocrystal in solution and in sustained release matrix tablets.

Methods

The polymorphic transitions of the CBZ-NIC cocrystal and its crystalline properties were examined by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Raman spectroscopy, and scanning electron microscopy (SEM).

Results

The apparent CBZ solubility and dissolution rate of CBZ-NIC cocrystal were constant in different concentrations of HPMC solutions. In a lower percentage of HPMC in the matrix tablets, the CBZ release profile of the CBZ-NIC cocrystal was nonlinear and declined over time. With an increased HPMC content in the tablets, the CBZ-NIC cocrystal formulation showed a significantly higher CBZ release rate in comparison with the other two formulations of CBZ III and the physical mixture.

Conclusions

Because of a significantly improved dissolution rate of the CBZ-NIC cocrystal, the rate of CBZ entering into solution is significantly faster than the rate of formation of the CBZ-HPMC soluble complex in solution, leading to a higher supersaturation level of CBZ and subsequently precipitation of CBZ dihydrate.