Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.

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Pharmaceutical compounds are molecular solids that frequently exhibit polymorphism of crystal form. One high profile case of polymorphism was ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in 1996. In 1998, a lower energy, more stable polymorph (form II) appeared, causing slowed dissolution of the marketed dosage form and compromising the oral bioavailability of the drug. This event forced the removal of the oral capsule formulation from the market. We have carried out high-throughput crystallization experiments to comprehensively explore ritonavir form diversity. A total of five forms were found: both known forms and three previously unknown forms. The novel forms include a metastable polymorph, a hydrate phase, and a formamide solvate. The solvate was converted to form I via the hydrate phase by using a simple washing procedure, providing an unusual route to prepare the form I ''disappearing polymorph'' Crystals of form I prepared by using this method retained the small needle morphology of the solvate and thus offer a potential strategy for particle size and morphology control. C rystalline polymorphism, or the ability of a compound to exist in multiple solid-state structures (1, 2), has significant impact on the physical properties, performance, and safety of an active pharmaceutical ingredient (API) and its formulated product(s). Hence, control of drug substance polymorphism is of major importance in drug discovery and development and is monitored carefully by the regulatory agencies. Thorough understanding of the relationship between the physical form and the physicochemical and͞or functional properties of an API is critical in selecting the most suitable form for development into a drug product. However, standard industry methods of solid form discovery rely on manual processes that are time consuming and often limited in scope because of the small amounts of material available at early stages of development. To overcome these challenges, high-throughput crystallization systems have been developed (3-5) permitting rapid and more comprehensive exploration of solid form diversity with only small amounts (Ͻ1 mg per trial) of API. Such systems also facilitate evaluation of the utility of all possible physical forms of a drug substance, enable rapid selection of the optimal solid form, and, thus, can accelerate the development process while minimizing the risk of downstream form-related manufacturing and performance issues (2).Ritonavir [Norvir, Abbott Laboratories, North Chicago, IL (5S,8S,10S,11S)-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester] is an important AIDS drug (6, 7) that garnered much attention when a previously unknown, thermodynamically more stable polymorph appeared unexpectedly, having serious implications for the marketed product and the patients taking the drug. During development and initial manufacture of ritonavir, only one monoclinic cryst...

Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.

A new gelcasting system based on aqueous-based aluminapoly(vinyl alcohol) (PVA) suspensions cross-linked by an organotitanate coupling agent has been developed. The chemorheological properties of this system exhibited a strong compositional dependence. A sol-gel phase diagram was established, which yielded the critical titanium concentration ([Ti] c ) required for gelation at a given PVA volume fraction as well as the minimum PVA volume fraction ( min PVA = 0.0245) and titanium concentration ([Ti] min = 9.984 × 10 −4 g of Ti/mL) below which gelation was not observed irrespective of solution composition. The gelation time of suspensions of constant PVA volume fraction ( soln PVA ) decreased with increased cross-linking agent concentration, temperature, and solids volume fraction. The steady-state viscosity and elastic modulus of polymer solutions ( soln PVA = 0.05) of varying [Ti] were well described by the percolation model, giving scaling exponents of 0.84 and 1.79, respectively. The steady-state elastic modulus of gelcasting suspensions, which provided a measure of their handling strength in the as-gelled state, increased with increased solids volume fraction.