Transformation under pressure: Discovery of a novel crystalline form of anthelmintic drug Praziquantel using high-pressure supercritical carbon dioxide.

Supercritical carbon dioxide (CO2) has been used as a processing technique to control polymorphism of pharmaceuticals. However, there are fewer reports of novel polymorphs being discovered by supercritical CO2 processing. As supercritical crystallization methods gain attention for potential in pharmaceutical processing, they may become a critical screening tool for discovery of new polymorphs. In this work, a case study is presented for a novel crystalline form of the anthelmintic drug, Praziquantel, found through supercritical CO2 processing. The novel form of Praziquantel was characterized by chromatography, nuclear magnetic resonance and infrared spectroscopy, X-ray powder diffraction, thermal analysis, and scanning electron microscopy. Furthermore, the novel form exhibited 13-20% improved solubility compared to commercial Form A between pH 1.6 and 7.5 and was physically stable under stressed conditions (40 °C and 75% relative humidity) for 7.5 weeks. Overall, this work showed that supercritical CO2 processing is a valuable tool to screen for novel, and possibly viable polymorphs of pharmaceutical compounds with improved properties.

Ternary Phase Diagram Development and Production of Niclosamide-Urea Co-Crystal by Spray Drying.

In this work, a ternary phase diagram was developed for a Niclosamide-urea co-crystal (NCS-UR) in isopropanol (IPA) using a combination of slurry and solvent addition methods. The ternary phase diagram showed that solubility of Niclosamide and urea differed by an order of magnitude in IPA, leading to an incongruently saturating system. Spray drying was explored as a method to generate NCS-UR. Co-crystals with small, uniform particle size were successfully prepared by spray drying from equimolar solutions with yield up to 73%. Co-crystals were phase pure by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) from all conditions explored. Somewhat similar particles were obtained at inlet temperature of 70 °C (mean size of 2.0 µm) compared to 85 °C (2.8-3.4 µm). Based on the TPD, isolating phase pure co-crystal through solution crystallization in IPA would require excess urea. However, spray drying did not require excess co-former. The in-vitro solubility of NCS-UR was compared to anhydrous NCS in biorelevant media. NCS-UR did not give improvement in solubility at 1 h or 24 h. Overall, this work showed that spray drying is a feasible process for preparing phase pure co-crystals for an incongruently saturating system and simultaneously generating micron size particles.

Characterization of new crystalline forms of hydroxyprogesterone caproate.

A systematic polymorph screening process was conducted on the steroid hydroxyprogesterone caproate, which had only one previously described orthorhombic crystalline form (A), in order to fully elucidate its solid state properties. Cooling, anti-solvent and evaporative techniques largely reproduced the same polymorph, but slurries in various solvents over two days produced a new triclinic form (B). Experiments at different temperatures in ethyl acetate or isopropyl alcohol confirmed this was an enantiotropic system with a transition temperature of approximately 30°C. DSC was used to confirm the transition of Form B to Form A below the melting point. Form B was the thermodynamically stable form at room temperature, and 8% less soluble in a non-aqueous solvent mixture. In viscous solvents used commercially to dissolve the oil-soluble steroid for injection, solutions near the solubility limit can remain supersaturated after exposure to cooler temperatures for months. In resolving the crystalline structure of Form A, a third conformational polymorph was detected that exists only at -133 to -143°C; this monoclinic form was designated Form C, and converts back to Form A upon warming to room temperature. These studies have increased the understanding of this drug and how the polymorphs may affect its physical stability in different dosage forms.

A novel process for preparation of fatty acid oil mixture in solid form.

The present study describes a novel and scalable process for preparation of omega-3 and omega-6 fatty acids in solid form. The process involves multiple steps consisting of combining the oil with a metal base in alcohol to form a solution, followed by addition of reaction mixture to acetonitrile (anti-solvent) to form a slurry and further separating the solid through filtration. This process results in formation of a flowable solid with yield of 44-76% depending on the procedure employed. The fatty acid profile of the calcium and magnesium salts was stable after one year of storage in ambient conditions. The type of solvent and anti-solvent employed in such process has tremendous effect on the resulting solid texture, which could range from complete gum to a workable, filterable solid. It was also demonstrated that increasing the concentration of base in alcohol reduces the amount of residual acetonitrile in the solid.

Aminodifluorosulfinium salts: selective fluorination reagents with enhanced thermal stability and ease of handling.

Diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M) are crystalline fluorinating agents that are more easily handled and significantly more stable than Deoxo-Fluor, DAST, and their analogues. These reagents can be prepared in a safer and more cost-efficient manner by avoiding the laborious and hazardous distillation of dialkylaminosulfur trifluorides. Unlike DAST, Deoxo-Fluor, and Fluolead, XtalFluor reagents do not generate highly corrosive free-HF and therefore can be used in standard borosilicate vessels. When used in conjunction with promoters such as Et(3)N.3HF, Et(3)N.2HF, or DBU, XtalFluor reagents effectively convert alcohols to alkyl fluorides and carbonyls to gem-difluorides. These reagents are typically more selective than DAST and Deoxo-Fluor and exhibit superior performance by providing significantly less elimination side products.

Thermodynamic modeling of activity coefficient and prediction of solubility: Part 2. Semipredictive or semiempirical models.

The solubility of stearic acid, ranitidine hydrochloride, and stavudine were predicted in selected organic solvents. The experimental solubility data of stearic acid and ranitidine hydrochloride were reported in previous work of the authors and stavudine's solubility was measured in this work. Equilibrium aqueous solubility of crystalline stauvudine was determined at controlled temperatures by stirring and filtration, with spectrophotometric quantification. The new model developed in Part 11 of this communication was modified as a semipredictive model with two adjustable parameters. Predicting the solubility data with the NRTL model using just one experimental point resulted in a big error while the modified new model and the UNIQUAC model showed much smaller errors. A new method was proposed in this work for predicting the solubility data of all polymorphs of a given compound using the experimental solubility data of one of the polymorphs of the same chemical compound. Although in general, the UNIQUAC model predictions were marginally superior, the new model is simpler and does not require the molecular parameters such as Van der Waals area and volume. The solubility prediction in a mixture of solvents using the NRTL and UNIQUAC models was also discussed.

Thermodynamic modeling of activity coefficient and prediction of solubility: Part 1. Predictive models.

A new activity coefficient model was developed from excess Gibbs free energy in the form G(ex) = cA(a) x(1)(b)...x(n)(b). The constants of the proposed model were considered to be function of solute and solvent dielectric constants, Hildebrand solubility parameters and specific volumes of solute and solvent molecules. The proposed model obeys the Gibbs-Duhem condition for activity coefficient models. To generalize the model and make it as a purely predictive model without any adjustable parameters, its constants were found using the experimental activity coefficient and physical properties of 20 vapor-liquid systems. The predictive capability of the proposed model was tested by calculating the activity coefficients of 41 binary vapor-liquid equilibrium systems and showed good agreement with the experimental data in comparison with two other predictive models, the UNIFAC and Hildebrand models. The only data used for the prediction of activity coefficients, were dielectric constants, Hildebrand solubility parameters, and specific volumes of the solute and solvent molecules. Furthermore, the proposed model was used to predict the activity coefficient of an organic compound, stearic acid, whose physical properties were available in methanol and 2-butanone. The predicted activity coefficient along with the thermal properties of the stearic acid were used to calculate the solubility of stearic acid in these two solvents and resulted in a better agreement with the experimental data compared to the UNIFAC and Hildebrand predictive models.

Stavudine.

The crystal structure of the title compound (systematic name: 2',3'-didehydro-2',3'-deoxythymidine), C10H12N2O4, consists of two molecules in the asymmetric unit bound together by hydrogen bonds. The conformational geometry differentiates this form of stavudine from its two previously published polymorphs. In addition, a different hydrogen-bonding scheme is observed compared with the previous two structures. This polymorph is the thermodynamically most stable form of the antiviral drug, as evidenced by differential scanning calorimetry (DSC) and IR data.

An approach to solvent screening for crystallization of polymorphic pharmaceuticals and fine chemicals.

It is desirable to have a systematic approach for predicting or interpreting the effect of the solvents on the production of polymorphs. A method based on the atomic electronegativity is suggested that calculates the partial charge distribution in the solute and solvent molecules. Using the calculated partial charges, correlations are developed to predict the hydrogen bonding ability of the solute and/or solvent molecules. The predictive capability of the proposed correlations is compared with the results of a quantum mechanics approach. Selection of the right solvent may play a significant role in the formation of a desirable polymorph or solvate. The most important properties of class 2 and 3 solvents of International Conference on Harmonization (ICH) for crystallization of polymorphic compounds are listed in this paper. The partial charge calculation has been used as a tool for analyzing the solvent impact on polymorphic isolation of two compounds: ranitidine hydrochloride (H2 receptor antagonist) and stearic acid (used as excipients or in coating the tablets).

Improving the filterability and solid density of ranitidine hydrochloride Form 1.

Ranitidine hydrochloride Form 1 produced by the original method (Price et al., 1978 US patent) has poor filtration and drying characteristics, which make it less desirable commercially in comparison with Form 2. This article shows that the operating parameters have significant influence on the final properties of Form 1. In terms of filterability and solid bulk density, it was found that at a higher temperature (approximately 48 degrees C), the viscosity of the slurry decreased and improved product quality as compared with operating at room temperature (approximately 25 degrees C). It was found that the rapid addition of acid to the ranitidine base increased product density but led to higher residual solvent inclusion. The presence of excess ranitidine base in the solution and also the manner of reactant addition had a significant influence on the onset of nucleation and the rate of crystallization. The best results in terms of filterability and bulk solid density were obtained using an initial pH of 5.3 and then increasing it to 6.3-6.4 after the onset of nucleation.