PublicationsWith over 10 years of industry experience, our Solid Form Sciences team consists of accomplished chemical engineers proficient in solid state technologies and molecular polymorphism, including crystallization expertise and thermodynamic & kinetics modeling. Listed below is a selection of publications authored by members of the JMPS solid form team.
An approach to solvent screening for crystallization of polymorphic pharmaceuticals and fine chemicals
Polymorph Screening - Comparing a Semi-Automated Approach with a High Throughput Method
Concomitant Crystallization of ROY on Patterned Substrates
Chiral Self Assembled Monolayers as Resolving Auxiliaries in the Crystallization of Valine
Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer
Improving the Filterability and Solid Density of Ranitidine Hydrochloride Form 1
Polymorphic Behavior and Crystal Habit of an Anti-Viral-HIV Drug- Stavudine
Characterization of Tautomeric Forms of Ranitidine Hydrochloride- Thermal Analysis, Solid-State NMR, X-ray
Thermodynamic Modeling of Activity Coefficient and Prediction of Solubility Part 1- Predictive Models
An approach to solvent screening for crystallization of polymorphic pharmaceuticals and fine chemicals
Mahmoud Mirmehrabi, Sohrab Rohani Journal of Pharmaceutical Sciences, 2005, 94(7):1560-1576
DOI:10.1002/jps.20371 Abstract
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).
Polymorph Screening - Comparing a Semi-Automated Approach with a High Throughput MethodAlejandro J. Alvarez , Aniruddh Singh and Allan S. Myerson Crystal Growth & Design, 2009, 9(9): 4181–4188
DOI: 10.1021/cg900421v Abstract
Polymorph screening studies of sulfathiazole, mefenamic acid, flufenamic acid, and ROY were carried out using a semi-automated apparatus. Cooling crystallization and slurry aging experiments were conducted with varying process conditions and a selection of 16 diverse solvents to find as many polymorphic forms as possible. Results yielded four out of five polymorphs of sulfathiazole, both polymorphs and a solvate of mefenamic acid, four out of the seven stable forms of ROY, as well as the two most commonly encountered polymorphs and a solvate of flufenamic acid. The results obtained in this study were compared with a novel high throughput method based on patterned substrates of self-assembled monolayers.(17, 32, 38) It was shown that in the case of sulfathiazole and mefenamic acid the same number of polymorphs were obtained using the two approaches. In the case of ROY, the semi-automated approach was not able to produce three of the forms found using the patterned self-assembled monolayers (SAMs) method. These three forms were found in fewer than 1% of approximately 10?000 experiments performed using the high throughput approach and thus will be very difficult to find in the 58 experiments performed using the semi-automated approach. Results of this study demonstrate that the simple semi-automated approach of 60 experiments described in this work is suitable for early stage polymorph screening as it was able to reproduce effectively the diversity of polymorphs in model compounds.
Concomitant Crystallization of ROY on Patterned SubstratesAniruddh Singh , In Sung Lee and Allan S. Myerson Crystal Growth & Design, 2009, 9(2): 1182–1185
DOI: 10.1021/cg801055x Abstract
In this study, we demonstrate how increasing the number of crystallization trials can help crystallize polymorphs which may not be obtained in a fewer number of trials due to statistical reasons. Crystallization experiments were conducted using patterned substrates of self-assembled monolayers (SAMs) with solutions of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (known as ROY for its red, orange, and yellow crystals) in dimethylsulfoxide (DMSO). The patterned bifunctional surface was immersed and slowly withdrawn from undersaturated solutions. The solution preferentially wetted the metallic islands, and as the solvent evaporated, ROY crystals exclusively nucleated on the lyophilic metallic islands. Raman microscopy was utilized to characterize the crystalline form on each metallic island. In one of the experiments, over 10?000 islands were analyzed, and we calculated the probability of crystallizing a particular polymorph on an island. We were able to crystallize six of the seven stable polymorphs of ROY using this method, including form YT04, which to the best of our knowledge, has never been obtained from solution crystallization.
Chiral Self Assembled Monolayers as Resolving Auxiliaries in the Crystallization of ValineAniruddh Singh, Allan S Myerson Journal of Pharmaceutical Sciences. 2010, 99(9): 3931-3940
DOI: 10.1002/jps.22237 Abstract
Chiral drugs are a subgroup of drug substances that contain one or more chiral centers. For reasons of safety and efficacy, the pure enantiomer is usually preferred over the racemate in many marketed dosage forms. Thus, resolution of racemic mixtures is an active area of research. In this work, chiral self assembled monolayers (SAMs) on gold were employed as resolving auxiliaries in the crystallization of the amino acid valine. Results showed the ability to obtain one enantiomer in excess on the crystals grown on the chiral SAMs when starting with racemic solutions. The enantiomer obtained in excess was the one having opposite chirality to the monolayer being used. In addition, it was possible to obtain crystals of the pure enantiomer when starting with a solution having an enantiomeric excess value of 50%. Control experiments carried out without chiral SAMs showed that at equilibrium, mixtures of the pure enantiomer and racemic compound were obtained under these conditions. The enantiomer obtained on the chiral SAMs was the one that was initially present in excess regardless of the chirality of the monolayer being used.
Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer
Alejandro J. Alvarez, Aniruddh Singh, and Allan S. Myerson Crystal Growth & Design, 2011, 11(10): 4392–4400
DOI: 10.1021/cg200546g Abstract
Crystallization processes can be batch or continuous. Potential advantages such as operating at steady state, small equipment size (relative to batch), and ability to recycle are encouraging the pharmaceutical industry to investigate continuous processes. In this work, a continuous cooling crystallization process for the immunosuppressant drug cyclosporine was developed. A multistage mixed suspension mixed product removal (MSMPR) crystallizer was employed which allowed simple analysis of kinetic parameters employing the population balance. Experimentally, the continuous crystallization system was able to operate without any clogging issues for more than four residence times. The experimental yield and purity of the crystals was determined as 71% and 96%, respectively (without recycle) and 87% and 94%, respectively (with recycle). In a batch cooling crystallization experiment, carried out under conditions similar to those of the continuous experiment without recycle, the experimental yield and purity of the crystals were 74% and 95%, respectively. The equilibrium distribution coefficients of cyclosporine impurities were measured experimentally as a function of impurity % of the starting solution. The distribution coefficients increase with a decrease in the purity of the starting solution, indicating a decrease in purification. The MSMPR model was used to estimate the nucleation and crystal growth rate kinetic parameters for cyclosporine crystallization and to evaluate the effect of process conditions on the purity of the crystals and the process yield. Results showed that the temperature of the third stage has a large impact on the final purity of the crystals. As the temperature of the third stage increases, the purity of the crystals also increases while the yield of the process decreases. The effect of recycle ratio on both crystal purity and process yield was also evaluated. A 93% process yield was obtained with a recycle ratio of 0.9. The yield of the process can be significantly improved by increasing the recycle ratio while the crystal purity decreases.
Improving the Filterability and Solid Density of Ranitidine Hydrochloride Form 1Mahmoud Mirmehrabi, Sohrab Rohani, K. S. Keshava Murthy, Bruno Radatus Journal of Pharmceutical Sciences, 2004, 93:1692–1700
DOI: 10.1002/jps.20074 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
Mahmoud Mirmehrabi, Sohrab Rohani, K. S. Keshava Murthy, Bruno Radatus Crystal Growth & Design, 2006, 6(1): 141–149
DOI: 10.1021/cg050242g 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.
Characterization of Tautomeric Forms of Ranitidine Hydrochloride- Thermal Analysis, Solid-State NMR, X-ray
Mahmoud Mirmehrabi, Sohrab Rohani, K. S. Keshava Murthy, Bruno Radatus Journal of Crystal Growth, 2004, 260(3): 517-526
DOI: 10.1016/j.jcrysgro 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 is configurational rather than conformational. It also showed explosive type of degradation at the melting point of both forms. Solid-state NMR studies suggest that Form 2 contains molecular disorder whereas Form 1 may be more ordered. A single crystal X-ray study confirms the disorder in Form 2 but a similar study on Form 1 could not be performed and its suspected order can only be inferred. It was found that significant amounts of strongly polar solvents such as methanol and water would favour the production of Form 2; while anhydrous less polar or non-polar solvents will result in the production of Form 1. Chloride ion acts as the bridge between the individual molecules of RAN-HCl in the crystal structure of Form 2.
Thermodynamic Modeling of Activity Coefficient and Prediction of Solubility Part 1- Predictive Models
Mahmoud Mirmehrabi, Sohrab Rohani, Luisa Perry Journal of Pharmaceutical Sciences, 2006, 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.
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