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Sulfamethazine (SMT) is a sulfonamide antibacterial drug used to treat or prevent infections in both humans and animals. However, SMT exhibits unfavorable taste and poor compaction behavior. To ove...

In an effort to develop a tablet product of celecoxib by overcoming its poor physicochemical properties using a pharmaceutically acceptable solvate, we isolated two stoichiometric N-Methyl-2-Pyrrol...

Successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution chara...

An l-proline cocrystal of celecoxib was identified based on a computational approach for predicting crystal mechanical properties in order to significantly reduce the punch sticking propensity of c...

Two conformational polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) exhibited similar morphology but strikingly different mechanical flexibility, where the yellow needl...

The aim of this study was to design and evaluate a cocrystal capable of releasing a highly water soluble drug, isoniazid (INH), over a period of longer than several hours by forming a cocrystal wit...

Two new salts of ligustrazine (tetramethylpyrazine, TMP) with the sweeteners, saccharine (SAC) and acesulfame (ACS), have been synthesized through the anion exchange reaction. Single crystals of the new forms were prepared, and their structures were determined. The stability of the new salts against heat and humidity was tested and compared to the commercial hydrochloride and phosphate salts. The sublimation kinetics at various temperatures was analyzed using the Arrhenius equation. The results indicated that TMP-ACS exhibits significantly reduced sublimation tendency and hygroscopicity, which make it a more suitable salt for developing a tablet with acceptable shelf stability than the salts currently used in commercial products.

Sulfamethizole (SMZ) is an antibiotic drug with good solubility but short in vivo half-life. Thus, reducing the dissolution rate is expected to improve bioavailability and therapeutic activity thro...

The crystal structures of four INZ cocrystals with analogous crystal coformers were probed to understand the relationships among molecular packing, H-bonding dimensionality, single-crystal plastici...

The crystal growth kinetics of amorphous celecoxib (CEL), an anti-inflammatory BCS class II drug, was systematically investigated for developing effective stabilization strategies to enhance solubi...

Cocrystallization represents an emerging approach to tackle the issues associated with pharmaceutical product performance and processing, owing to its capability of modifying a variety of physicochemical properties. In this study, we sought to modify the crystal form of itraconazole (ITZ) with suberic acid (SUB) via rapid solvent removal methods, namely rotary evaporation and spray drying. A phase pure ITZ-SUB cocrystal, which could not be obtained by traditional cocrystallization methods, was successfully prepared by rotary evaporation. The new cocrystal was confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. Spray drying was further employed for particle engineering of ITZ-SUB to achieve optimal pulmonary delivery. By manipulating the critical processing parameters, inhalable ITZ-SUB agglomerates with a mass median aerodynamic diameter of 2.56 ± 2.27 μm and fine particle fraction of 64.10% w/w were reproducibly prepared. The inhalable po...

Spherical cocrystallization (SCC), an integrated crystal and particle engineering approach, was successfully applied to generate spherical cocrystal agglomerates (SCA) between a poorly soluble drug...

Griseofulvin (GSF) is a high dose drug exhibiting poor flowability and tabletability, which makes formulating a high drug loading tablet challenging. In using spherical crystallization to improve f...

Recent advances in crystal engineering by cocrystallization have offered a promising approach for tackling undesirable physicochemical properties of drug substances. In this study, various structur...

Improving taste and tuning physicochemical properties of active pharmaceutical ingredients (API) by forming new salts or cocrystals with an artificial sweetener, such as saccharine (Sac) and acesulfame (Acs), is an effective crystal engineering strategy for facilitating successful delivery of bitter drugs. However, the number of reported solid forms of Acs is curiously lower (29) than that of Sac (275). An analysis of the literature revealed that the preparation of salts or cocrystals of Acs was hindered by the difficulty and cost in preparing Acs free acid from commercially available potassium salt (Acs-K). Here, we evaluated the broad applicability of an anion exchange reaction for preparing Acs solid forms using nine model compounds. In all cases, we successfully prepared Acs crystals, based on single crystal structure determination, simply from ion exchange between Acs-K and corresponding salts. The proton transfer propensity, hydrogen-bonding pattern, and amide group keto–enol tautomerism in the Acs ...

The relationship between crystal structure and mechanical properties is commonly studied by identifying slip planes through inspecting crystal structures visually, with a focus on the hydrogen bonding interactions. While useful, the visualization method lacks quantitative insight, and the identification of slip planes is subjective. Sometimes, crystal plasticity predicted from structure visualization does not match experimental crystal plasticity and powder tabletability as observed in three polymorphic systems, 6-chloro-2,4-dinitroaniline, indomethacin, and febuxostat. Here, we explored the feasibility of more reliably identifying slip planes by the energy framework approach, combined with analysis of potential slip layer topology. In all three cases, this new approach identified slip planes that are consistent with the observed mechanical plasticity and compaction behavior. Thus, it is superior to the visualization method for crystal structure analysis aimed at identifying active slip planes in organic ...

Clear understanding of the relationships among crystal structure, mechanical properties, and tableting performance is of enormous importance for successful development of tablet products. This study was aimed at systematically examining such relationships using four salts of diphenhydramine (DPH), a first-generation H-receptor antagonist, i.e., hydrochloride (DPH-HCl), citrate (DPH-Cit), saccharinate (DPH-Sac), and acesulfamate (DPH-Acs). The conformation and intermolecular interactions of DPH as well as crystal packing in the four salts were considerably different. Both the energy framework and visualization of the crystal structure revealed the greatest plasticity of DPH-Acs, which was characterized by drastically different intermolecular interactions in orthogonal directions. This was consistent with its facile bending behavior and the lowest hardness. The most plastic DPH-Acs also exhibited the best tabletability, which was accompanied by greater compressibility and compactibility as well as smaller e...

Highly soluble cocrystals can be used to improve bioavailability of a poorly soluble drug, through generating supersaturation, when absorption is limited by drug dissolution. Dihydromyricetin (DMY) is a biopharmaceutics classification system (BCS) IV drug, exhibiting dissolution limited absorption. Two novel soluble cocrystals of (±)DMY with caffeine and urea were prepared, and their physicochemical properties were evaluated for suitability in formulation development. Although having a much higher solubility than (±)DMY, both cocrystals undergo rapid precipitation during dissolution and form the poorly soluble (±)DMY dihydrate in aqueous media. This negates the potential advantage offered by the high solubility of the two cocrystals in enhancing the dissolution rate and in vivo bioavailability. To solve this problem, we have systematically evaluated suitable crystallization inhibitors to maintain the supersaturation generated by cocrystal dissolution over a prolonged period of time. At 37 °C, an approxima...

Tuning mechanical performance of molecular materials is currently attractive owing to their practical applications in pharmaceutical, food, and fine chemical industries and optoelectronics. Here we employed a crystal engineering approach to transform four food flavouring agents, vanillin isomers, from brittle to soft solids by forming co-crystals with 6-chloro-2,4-dinitroaniline (cda). The series includes vanillin (van), ethylvanillin (evan), iso-vanillin (ivan), as well as a Schiff base of ortho-vanillin (ovan) with ethylene diamine (sb-ovan). All the co-crystals adopt flat two-dimensional (2D) layer packing, except the sb-ovan:cda, which adopts a corrugated layer packing with the presence of slip planes. The mechanical properties of the co-crystals were studied by (1) a qualitative method, (2) nanoindentation, and (3) powder compaction techniques, which allowed for successfully establishing the relationship among crystal structure, mechanical properties, and tablet tensile strength. The simple qualitati...

A highly soluble cocrystal of a poorly soluble drug has the potential to improve the dissolution rate and bioavailability. Reaping the potential dissolution advantage of soluble cocrystals is challenged by the precipitation of the parent drug during dissolution. Using the carbamazepine–nicotinamide cocrystal, we show that the use of excess coformer can be an effective strategy for eliminating precipitation during dissolution by taking advantage of the “common coformer effect”. When excess coformer is present, the solubility of the cocrystal is depressed, which leads to a lower degree of supersaturation. At an appropriate level, precipitation can be prevented and improved dissolution is realized.

Successful cocrystallization between a salicylate salt with salicylic acid and chemically distinct carboxylic acids suggests the robustness of the carboxylic acid-carboxylate supramolecular synthon. This type of robust synthon involving charge-assisted hydrogen bonding interactions has the potential to significantly expand the solid-state landscape of ionizable molecules.

Intrinsic dissolution rate (IDR) is a useful technique to differentiate the solid forms of a drug. In the present study, the impact of crystal habit and crystal size on IDR of celecoxib (CEL) in different media was assessed. The IDR of plate-shaped CEL crystals (CEL-P) (53.4 ± 6.7 μg/min/cm2) was 46.3% higher than that of acicular crystals (CEL-A) (36.5 ± 1.7 μg/min/cm2) in pH 12 phosphate buffer. Contact angle experiments and values of dispersive and polar components of surface free energy indicated better wettability of CEL-P compacts than CEL-A. Higher IDR and better wettability of CEL-P were attributed to favorable exposure of hydrophilic crystal facets on compact surface, due to preferred orientation during compaction. In contrast to native samples, milled CEL-A (MCEL-A) and milled CEL-P (MCEL-P) showed similar IDR. Interestingly, IDR of CEL-A (36.5 ± 1.7 μg/min/cm2) and MCEL-A (35.64 ± 5.09 μg/min/cm2) did not show any significant difference (p > 0.05). However, IDR of CEL-P (53.4 ± 6.7 μg/min/cm2) ...

The existence of a cocrystal between curcumin (CUR) and phloroglucinol (PHL) was suspected but could not be demonstrated in a recent systematic effort to synthesize novel curcumin cocrystals. We hypothesize that the elusive CUR–PHL cocrystal is a kinetically stable form that can be prepared by trapping it using a fast solvent removal crystallization process. The polarity of crystallization solvent and relative solubility of cocrystal formers in the solvent appear to be critical parameters governing the phase purity of the resulting cocrystal. Organic solvents of higher polarity and in which the cocrystal formers exhibited congruent solubility tended to afford a purer cocrystal phase. Essentially phase-pure CUR–PHL cocrystals were successfully obtained from acetone, and their 1:1 stoichiometry was confirmed by differential scanning calorimetry and solid state nuclear magnetic resonance spectroscopy. Compared with the individual component phases, the cocrystal displayed reduced hygroscopicity and improved t...

Lamivudine (LMV), a cytosine derivative and a reverse transcriptase inhibitor, faces the challenge of inefficient purification after its chemical synthesis. Currently available methods of purification involve salt formation (salicylate or oxalate) followed by treatment with a toxic base, triethyl amine (TEA), to neutralize the protonated LMV. Any reduction in the use of TEA will make the purification process greener and more economical. In this context, we designed and successfully isolated a new and elusive 4:1 CAB cocrystal between LMV and oxalic acid (OXA) that has the potential to significantly improve the efficiency of the LMV purification process. The new CAB cocrystal of LMV was efficiently produced by carefully controlling the ratio of LMV to OXA in the crystallization medium. Compared to salts currently used for purification, much less TEA is required for the 4:1 CAB cocrystal (LMV/LMVH+/OXA2– at 2:2:1 mole ratio) because only half of the LMV is protonated that requires TEA treatment.

The 1:1 cocrystal between piroxicam and saccharin exhibits significantly deteriorated powder compaction properties compared to both coformers. The molecular origin of this effect is revealed by a systematic investigation of crystal mechanical properties, probed with nanoindentation, and crystal structure analysis. The order of bulk powder tabletability of the three materials is identical to that of single crystal plasticity (saccharin > piroxicam > cocrystal). The lowest plasticity of the cocrystal is confirmed by its highest crystal hardness and the highest yield strength. The low plasticity of the cocrystal is attributed to structural packing features that discourage plastic deformation. This work demonstrates that cocrystallization, even though it may be useful to improve pharmaceutically relevant properties, must be carefully evaluated to avoid unexpected problems in formulation and drug product manufacturing due to compromised mechanical properties.

Poor biopharmaceutical performance of Biopharmaceutical Classification System (BCS) class II drug molecules is a major hurdle in the design and development of pharmaceutical formulations. Anisotropic surface chemistry of different facets in crystalline material affects physicochemical properties, such as wettability, of drugs. In the present investigation, a molecule-centered approach is presented toward crystal habit modification of celecoxib (CEL) and its effect on oral bioavailability. Two crystal habits of CEL, acicular crystal habit (CEL-A) and a plate-shaped crystal habit (CEL-P), were obtained by recrystallization from toluene at 25 and 60 °C, respectively. Compared to CEL-A, CEL-P exhibited significantly faster dissolution kinetics in aqueous media and significantly higher Cmax and shorter Tmax in an oral bioavailability study. The significant enhancement in dissolution and biopharmaceutical performance of CEL-P was attributed to its more abundant hydrophilic surfaces compared to CEL-A. This concl...

Cytosine, a nucleobase, can exhibit two protonated states, cytosinium and hemicytosinium. The controlled synthesis of structures containing these ions is highly desired but not yet achieved. Herein, we report strategies for robust synthesis of both structures by controlling the strength of an acid used for protonation and its concentration. The duplex structure is always obtained by using an acid with a pKa > 4.2, which is incapable of disrupting the relatively stable duplex structure. When stronger acids (pKa < 4.19) are used, the duplex structure is obtained by controlling acid concentration to protonate a half of cytosine in solution, and the cytosinium structure is obtained with excess acid. These strategies are successfully applied to synthesize both forms of 5-fluorocytosine, an antifungal drug. The hemicytosinium structure exhibits superior physicochemical properties than the parent drug and the cytosinium salt. These strategies may be useful to prepare materials important to various branches of sc...

The December 2011 release of a draft United States Food and Drug Administration (FDA) guidance concerning regulatory classification of pharmaceutical cocrystals of active pharmaceutical ingredients (APIs) addressed two matters of topical interest to the crystal engineering and pharmaceutical science communities: (1) a proposed definition of cocrystals; (2) a proposed classification of pharmaceutical cocrystals as dissociable “API-excipient” molecular complexes. The Indo–U.S. Bilateral Meeting sponsored by the Indo–U.S. Science and Technology Forum titled The Evolving Role of Solid State Chemistry in Pharmaceutical Science was held in Manesar near Delhi, India, from February 2–4, 2012. A session of the meeting was devoted to discussion of the FDA guidance draft. The debate generated strong consensus on the need to define cocrystals more broadly and to classify them like salts. It was also concluded that the diversity of API crystal forms makes it difficult to classify solid forms into three categories that...

By the formation of a 1:1 cocrystal of caffeine and methyl gallate, we demonstrated that powder compaction properties could be profoundly improved. The selection criterion for cocrystal exhibiting superior compaction properties was the presence of slip planes in crystal structure. Bulk cocrystal was prepared by suspending powders of the two pure compounds in ethanol. Fine powders of similar particle size distribution were compressed. Within the whole range of compaction pressure, the tablet tensile strength of methyl gallate was very poor ( 180 MPa, severe lamination of caffeine tablets suddenly occurred. Tablet tensile strength dropped sharply at >240 MPa. In contrast, the tabletability of the cocrystal was excellent over the entire pressure range. Tablet tensile strength of the cocrystal was ∼2 times that of caffeine at