How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability.

Cocrystals of a weakly basic drug (nevirapine) with acidic coformers are shown to alter the solubility dependence on pH, and to exhibit a pHmax above which a less soluble cocrystal becomes more soluble than the drug. The cocrystal solubility advantage can be dialed up or down by solution pH.

Crystallization pathways and kinetics of carbamazepine-nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies.

The work presented here was motivated by the premise that the amorphous state serves as a medium to study cocrystal formation. The molecular mobility inherent to amorphous phases can lead to molecular associations between different components such that a single crystalline phase of multiple components or cocrystal is formed. Cocrystallization pathways and kinetics were investigated from amorphous equimolar phases of carbamazepine and nicotinamide using hot-stage polarized microscopy (HSPM), hot-stage Raman microscopy (HSRM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). Nonisothermal studies revealed that amorphous phases generate cocrystals and that thermal history affects crystallization pathways in significant ways. Two different pathways to cocrystal formation from the amorphous phase were identified: (1) at low heating rates (3 degrees C/min) a metastable cocrystalline phase initially nucleates and transforms to the more stable cocrystalline phase of CBZ-NCT, and (2) at higher heating rates (10 degrees C/min) individual components crystallize, then melt and the stable cocrystalline phase nucleates and grows from the melt. Isothermal studies above the T(g) of the amorphous equimolar phase also confirm the nucleation of a metastable cocrystalline phase from the amorphous state followed by a solid phase mediated transformation to the stable cocrystalline phase. Cocrystallization kinetics were measured by image analysis and by thermal analysis from small samples and are described by the Avrami-Erofeev model. These findings have important implications for the use of amorphous phases in the discovery of cocrystals and to determine the propensity of cocrystallization from process-induced amorphization.

Surfactant-facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph.

The influence of two structurally different anionic surfactants on the anhydrous-to-dihydrate transformation of carbamazepine (CBZ) was investigated. The surfactants studied were sodium lauryl sulfate (SLS), a surfactant commonly used in compendial dissolution methods, and sodium taurocholate (STC), an important surfactant in the solubilization and absorption of drugs and lipids in the gastrointestinal tract. Results show that both surfactants promoted the crystallization of CBZ dihydrate [CBZ(D)] during dissolution of the anhydrous monoclinic polymorph [CBZ(A)]). Examination of crystal surfaces showed that SLS facilitated the surface-mediated nucleation of CBZ(D) on CBZ(A) crystals at surfactant concentrations below the critical micelle concentration (cmc). Solubilization of a dye and related color changes provided visual evidence for adsorbed SLS assemblies on CBZ(A) crystal faces below the cmc. Above the cmc, both surfactants promoted the transformation by increasing the bulk nucleation of CBZ(D). STC changed the crystal morphology of CBZ(D) from acicular to prismatic, depending on STC concentration. Such morphology changes originate from interactions between STC and molecular structures of CBZ(D) crystal faces that interfere with the formation of a hydrogen-bonded chain of water molecules and carboxamide dimers.

Crystal engineering of the composition of pharmaceutical phases.

The carboxylic acid-pyridine supramolecular heterosynthon can be exploited to predictably generate binary crystalline phases involving rac-ibuprofen, rac-flurbiprofen or aspirin.

Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder.

This paper describes the kinetics of the solution-mediated phase transformation of the anhydrous monoclinic polymorph of carbamazepine (CBZ(A)) to the dihydrate crystal form (CBZ(D)). Monitoring both solution concentration and solid phase composition identified the steps and mechanisms that control the kinetic processes, and regulate the concentration of drug achieved during dissolution of the metastable solid phase, CBZ(A). The results show that the kinetics and the rate-controlling step for the transformation depend on grinding and storage conditions of CBZ(A). Grinding CBZ(A) shortened the transformation times and changed the rate-controlling step from crystallization of CBZ(D) to dissolution of CBZ(A). Grinding may cause various degrees of disorder in the form of lattice defects and/or amorphous regions. These disordered regions promote the anhydrous to dihydrate transformation by facilitating the surface nucleation of CBZ(D) on freshly ground CBZ(A) and on amorphous CBZ. The concentration-time profiles revealed aging effects on the solution-mediated transformation of ground CBZ(A) that were undetectable by diffraction and thermal analysis. These results have significant consequences on the concentration-time profiles of active pharmaceutical ingredients during dissolution of metastable solid phases, crystalline or amorphous.

Effect of initial buffer composition on pH changes during far-from-equilibrium freezing of sodium phosphate buffer solutions.

PURPOSE: This study aims to assess the pH changes induced by salt precipitation during far-from-equilibrium freezing of sodium phosphate buffers as a function of buffer composition, under experimental conditions relevant to pharmaceutical applications-sample volumes larger than a few microliters, experiencing large degrees of undercooling and supersaturation. METHODS: Buffer solutions were prepared by dissolving the monosodium and disodium phosphate salts in the appropriate ratios to obtain initial buffer concentrations in the range of 8-100 mM and pH values between 5.7 and 7.4 at 25 degrees C. Temperature and pH were monitored in situ during cooling to -10 degrees C (at a rate of 0.3 to 0.5 degrees C/min) and for 10-20 min after the sample reached the final temperature. Salt crystallization was confirmed by ion analysis and x-ray powder diffraction. RESULTS: Precipitation of Na2HPO4, 12H2O caused abrupt pH decreases after the onset of ice crystallization, at temperatures between -0.5 and -4.0 degrees C. Decreasing the initial buffer concentration and/or initial pH resulted in higher final pH values at -10 degrees C, farther removed from the equilibrium value of 3.6. At an initial pH of 7.4, the 50 and 100 mM buffer solutions reached a pH of 4.2 +/- 0.1 at -10 degrees C, whereas the 8 mM solutions reached a pH of 5.2 +/- 0.2. Solutions having an initial pH of 5.7 and initial buffer concentrations of 8 and 100 mM experienced less pH shifts upon freezing to -10 degrees C, with final pH values of 5.1 +/- 0.1 and 4.7 +/- 0.1, respectively. CONCLUSIONS: Precipitation-induced pH shifts are dependent on the concentrations (activities) of precipitating ions, and are determined by both initial pH and salt concentration. The ion activity product is a meaningful parameter when describing salt precipitation in solutions prepared by mixing salts containing precipitating and nonprecipitating ions.

Protein denaturation during freezing and thawing in phosphate buffer systems: monomeric and tetrameric beta-galactosidase.

During freezing in sodium and potassium phosphate (NaP and KP) buffer solutions, changes in pH may impact the stability of proteins. Since the degradation pathways for the model proteins, monomeric and tetrameric beta-galactosidase (beta-gal), chosen for this study are governed by conformational changes (i.e., physical instability) as opposed to chemical transformations, we explored how the stresses of freezing and thawing alter the protein's native structure and if preservation of the native conformation during freeze-thawing is a requisite for optimal recovery of activity. During freezing in NaP buffer, a significant pH decrease from 7.0 to as low as 3.8 was observed due to the selective precipitation of the disodium phosphate; however, the pH during freezing in KP buffer only increased by at most 0.3 pH units. pH-induced inactivation was evident as seen by the lower recovery of activity when freeze-thawing in NaP buffer as compared to KP buffer for both sources of beta-gal. In addition, we investigated the effects of cooling rate and warming rate on the recovery of activity for monomeric and tetrameric beta-gal. Optimal recovery of activity for the NaP samples was obtained when the processing protocol involved a fast cool/fast warm combination, which minimizes exposure to acidic conditions and concentrated solutes. Alterations in the native secondary structure of monomeric beta-gal as measured by infrared spectroscopy were more significant when freezing and thawing in NaP buffer as opposed to KP buffer. Conformational and activity analyses indicate that pH changes during freezing in NaP buffer contribute to denaturation of beta-gal. These results suggest that proteins formulated in NaP buffer should be frozen and thawed rapidly to minimize exposure to low pH and high buffer salts.

Growth and morphology of L-alanine crystals: influence of additive adsorption.

The effect of L-amino acids, as additives, on the crystal growth and morphology of L-alanine crystals has been studied. The crystal growth of L-alanine is described by the spiral growth mechanism. From examining the growth rate dependence on supersaturation at constant additive concentration, it is concluded that there is no change in the growth mechanism due to the presence of the different additives. L-Alanine crystals were grown both in the absence and in the presence of additives. The crystal morphology was characterized by optical goniometry assigning the different Miller indices to the well-developed crystal faces. The addition of L-amino acids selectively inhibits the development of certain L-alanine crystal faces. L-Alanine crystals grown in the presence of nonpolar amino acids, such as L-leucine, L-phenylalanine, and L-valine, at concentrations as low as 0.20 m (0.3%, w/w) develop the [120] faces, whereas the [010], [110], and [210] faces are not developed. The effect of these additives on the morphology of L-alanine is explained at the molecular level based on crystallographic considerations. The molecular structure of a face will determine the availability of sites that favor the adsorption of the additives. The availability of sites and their energy, on a particular crystal face, will determine the extent of adsorption. The growth rate of a crystal face is decreased by the adsorption of the additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystal growth kinetics of theophylline monohydrate.

The crystal growth kinetics of theophylline monohydrate from aqueous buffered supersaturated solutions were investigated at 10, 20, 30, and 40 degrees C. Crystallization experiments were carried out isothermally at pH 6. During growth the crystal count and size distributions were monitored in situ. The growth rate was evaluated from the rate of change of the size with time at a constant value of the size distribution. The growth rate is independent of the stirring rate and the activation energy for growth is higher than the value for simple diffusion, 14.3 and 4.4 kcal/mol, respectively. This indicates that crystal growth of theophylline monohydrate is controlled by a surface reaction mechanism rather than by solute diffusion in the bulk. The growth-rate dependence on the supersaturation was compared with crystal growth theories. The data are described by the screw dislocation model and by the parabolic law, suggesting a defect-mediated growth mechanism rather than a surface nucleation mechanism.

Evaluation of growth rate constants of oxalic acid dihydrate at constant supersaturation.

It is shown that at constant supersaturation during crystallization of oxalic acid dihydrate, the growth rate equation can be solved in closed form. At low degrees of supersaturation, where nucleation is negligible, the depletion of solute from solution is described by a cube root relationship and allows for calculation of the growth rate constant.

Crystallization kinetics of oxalic acid dihydrate: nonisothermal desupersaturation of solutions.

Oxalic acid dihydrate was dissolved in binary solvents (acetone:water and glycerol:water) at various saturation temperatures and then cured at higher temperatures. A temperature programmer was used to both heat and cool the solution in a linear fashion. Desupersaturation was followed as a function of time by measuring the changes in solution concentration, and number-based particle size distributions of the resulting crystals were then determined. A model based on the numerical evaluation of the nucleation and growth rates was developed which describes the amount of oxalic acid dihydrate precipitated with respect to time during nonisothermal crystallization. The model allows for calculation of the nucleation and growth rate constants when used with established values of the nucleation and growth orders.

Expected particle size distributions of crystals produced from nonisothermal recrystallization.

It is shown, using oxalic acid dihydrate as a model, that nonisothermal recrystallization of powders gives rise to particle size distributions which approach log-normality in many cases. The number of particles formed is, primarily, a function of the nucleation rate constants and the particle size distribution, i.e., the mean diameter and standard deviation are functions of the growth kinetic parameters.