The objectives of this study are to enhance the oral bioavailability of cilostazol (CLZ), which is a poorly soluble compound, by cocrystallization and to evaluate the correlation between the calculated solubility of the cocrystal by the solubility product (K sp ) and the complexation constant (K 11 ) and the performance of the cocrystal. Cocrystals of CLZ with 4-hydroxybenzoic acid (4HBA), 2,4-dihydroxybenzoic acid (2,4DHBA), and 2,5-dihydroxybenzoic acid (2,5DHBA) were prepared. Stoichiometric 1:1 structures were formed in the crystal packing of the three cocrystals according to single crystal X-ray diffraction. The calculated solubilities of the CLZ−4HBA cocrystal, CLZ−2,4DHBA cocrystal, and CLZ− 2,5DHBA cocrystal were 9.5-fold, 14.5-fold, and 34.3-fold higher than that of CLZ, respectively. Interestingly, the supersaturated dissolution profile in the nonsink condition was inversely correlated with the calculated solubility of the cocrystals, and the CLZ− 4HBA cocrystal, which mildly enhanced the solubility compared to the other cocrystals, effectively prolonged the supersaturation. The in vivo performance correlated with the in vitro dissolution profile, and the bioavailability of the CLZ−4HBA cocrystal in beagles was also significantly enhanced even when compared to the amorphous solid dispersion. The cocrystallization of CLZ could be an effective means to enhance the bioavailability, but excessive solubility enhancement was not preferable for the CLZ cocrystal.

No abstract

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/ or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

Crystallization is one of the most useful processes for the separation and purification of crystalline compounds. In crystallization processes, real-time monitoring is essential to obtain constant quality of crystalline compounds. This paper is the first to report in situ monitoring of crystalline transformations of active pharmaceutical ingredients by probe-type low-frequency Raman spectroscopy. In this study, carbamazepine was used as a model active pharmaceutical ingredient. We attempted to monitor the crystalline transformation of carbamazepine during heat treatment and the addition of solvent in a one-pot reaction. When carbamazepine form III was heated to 170 °C, the indicative spectrum of carbamazepine form I appeared over time. Subsequent addition of ethanol with heat treatment caused the carbamazepine form I spectrum to disappear. After cooling to room temperature, the spectrum of carbamazepine form III reappeared. To optimize the solvent ratio, we monitored carbamazepine form III as it dispersed into a mixture of ethanol/water with different compositions (75/ 25, 62.5/37.5, 50/50, 37.5/62.5, and 25/75 (v/v)). The spectra of carbamazepine dihydrate were observed in all solvent compositions. When the mixture of ethanol/water was 62.5/37.5 (v/v), the conversion time to carbamazepine dihydrate was fastest. Therefore, probe-type lowfrequency Raman spectroscopy can be used for the in situ monitoring of crystalline transformation and may become a useful process analytical technology technique.

Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood-brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [(3)H]naloxone exhibited saturability in a concentration-dependent manner (concentration range 0.5 microM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier-mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, K(t), was 2.99+/-0.71 mM; the maximum uptake rate, J(max), was 0.477+/-0.083 micromol/min/g brain; and the nonsaturable first-order rate constant, K(d), was 0.160+/-0.044 ml/min/g brain. The uptake of [(3)H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H(1)-antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [(3)H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L-carnitine or substrates for organic anion transport systems such as p-aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH-dependent and saturable influx transport system that is a selective transporter for cationic H(1)-antagonists is involved in the BBB transport of naloxone in the rat.