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Stavudine

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Mahmoud Mirmehrabi et. al.
Acta Crystallographica, Section C: Crystal Structure Communications, C61(12), 695-698

Abstract

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.

Characterization of Tautomeric Forms of Ranitidine Hydrochloride: Thermal Analysis, Solid-State NMR, X-ray

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Mahmoud Mirmehrabi, et. al. Journal of Crystal Growth, 260, 517-526

Abstract

The molecular structure of ranitidine hydrochloride (RAN-HCl) has an important influence on the growth of individual crystals and consequently the physical properties such as bulk solid density. This paper suggests that the correct structure of the nitroethenediamine moiety in the Form 2 RAN-HCl is a mixture of enamine and nitronic acid tautomers. Thermal analysis showed that the difference between the two forms Read More

Thermodynamic Modeling of Activity Coefficient and Prediction of Solubility: Part 2. Semi-Predictive or Semi-Empirical Models.

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Mahmoud Mirmehrabi et. al.
Journal of Pharmaceutical Sciences, 95(4), 798-809

Abstract

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 Read More

Thermodynamic Modeling of Activity Coefficient and Prediction of Solubility: Part 1. Predictive Models

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Mahmoud Mirmehrabi et. al.
Journal of Pharmaceutical Sciences, 95(4), 790-797

Abstract

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.

Solubility, Dissolution Rate and Phase Transition Studies of Ranitidine Hydrochloride Tautomeric Forms

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Mahmoud Mirmehrabi et. al.
International Journal of Pharmaceutics, 282(1-2), 73-85

Abstract

Understanding the polymorphic behavior of pharmaceutical solids during the crystallization process and further in post-processing units is crucial to meet medical and legal requirements. In this study, an analytical technique was developed for determining the composition of two solid forms of ranitidine hydrochloride using two peaks of Fourier transform infrared (FTIR) spectra without the need to grind the samples. Solubility studies of ranitidine hydrochloride showed that Form 2 has a higher solubility than Form 1. Solution-mediated transformation is very slow and occurs from Form 2 to Form 1 and not the reverse. No solid-solid transformation was observed due to grinding or compressing the pure samples of either forms and of a 50/50 wt.% mixture. Grinding was found to be a proper technique for increasing the bulk solid density of the ranitidine hydrochloride without the risk of solid-solid transformation. Dissolution rate found to be equally fast for both forms. The solubility data were modeled using the group contribution parameters and UNIversal QUAsi-Chemical (UNIQUAC) theory. There was a good agreement between the experimental solubility data of ranitidine hydrochloride and the results of UNIQUAC equation.

Improving the Filterability and Solid Density of Ranitidine Hydrochloride Form 1

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Mahmoud Mirmehrabi et. al.
Journal of Pharmaceutical Sciences, 93 (7), 1692-1700

Abstract
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 (~48°C), the viscosity of the slurry decreased and improved product quality as compared with operating at room temperature (~25°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.

Polymorphic Behavior and Crystal Habit of an Anti-Viral/HIV Drug: Stavudine

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Mahmoud Mirmehrabi et. al.
Crystal Growth and Design (American Chemical Society), 6(1), 141-149

Abstract

Different characterization methods (optical microscopy, Karl Ficher titration (KF), XRPD, and solid-state FTIR) were used to identify the two polymorphs and one hydrate of stavudine. The two forms are monotropically related, and form 1 is the stable polymorph. The effects of solvent, impurities, supersaturation, and mixing on the polymorphic occurrence of stavudine are investigated in detail. Hydrogen bonding analysis is employed to qualitatively predict the role of the solvent and structurally related impurities (thymine and thymidine) on polymorphism and crystal habit of stavudine crystals. The impurities showed significant changes in the crystal habit and crystal bulk density of stavudine but had no influence on the polymorphic structure. Depending on the degree of supersaturation at T = 25 °C, a specific polymorph or a mixture of forms 1 and 2 was obtained concomitantly.