Theoretical and Experimental Investigations on the Morphology of Pharmaceutical Crystals

Coombes, David S.; Catlow, C. Richard A.; Gale, Julian D.; Hardy, Martin J.; Saunders, Martin

doi:10.1002/jps.10148

Cited by 44 publications

(24 citation statements)

References 21 publications

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“…Predicting the relative free energy of polymorphs with molecular simulation is challenging (Karamertzanis et al 2008;Price 2008). Using single structures to calculate the zero point energy of bulk unit cells at 0 K may not give the best estimate of the relative free energy ranking of finite sized crystals at higher temperatures (van Eijck and Mooij 1995;Verwer and Leusen 2007;van Eijck 2001;van Eijck et al 2001;Coombes et al 2002;Woodley and Catlow 2008;Li et al 2011). Entropic effects may play a role in the relative stability of polymorphs at a given temperature.…”

Section: Discussionmentioning

confidence: 99%

Conversion of cellulose Iα to Iβ via a high temperature intermediate (I-HT) and other cellulose phase transformations

2011

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The observation that the hydrothermal conversion of cellulose Ia to cellulose Ib is irreversible has been assumed to be due to the relative free energy of these polymorph phases. We propose an alternative explanation: when cooling the high temperature phase, the barrier to forming Ib is much smaller than the barrier to forming Ia, so kinetics favor the formation of Ib. This explanation is consistent with all available experimental data, and is consistent with the general observation of polymer solid-solid phase transformations via metastable intermediate states. While cellulose Ib may be lower in free energy than Ia, this has not been shown experimentally. Phase transformations of other cellulose polymorphs may be subject to similar kinetic effects when converted via metastable intermediate states.

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Section: Discussionmentioning

confidence: 99%

Conversion of cellulose Iα to Iβ via a high temperature intermediate (I-HT) and other cellulose phase transformations

2011

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“…The latter sets the growth rate of a crystal face to be proportional to the absolute value of the attachment energy 12 which is defined as the energy released on the addition of a growth slice to the surface of a growing crystal, 13,14 and is estimated using intermolecular interactions between a molecule on the face and the bulk of the crystal. These early methods have been widely used to predict the crystal shape of pharmaceutical crystals, [15][16][17][18] with some of them being implemented in commercial computer programs. The great advantage of the aforementioned approaches is that they are based on sound physical principles, with all that is required to implement these models is the internal structure information of the crystal, such as unit cell parameters, fractional atomic coordinates and symmetry information.…”

Section: Crystal Morphology and Its Predictionmentioning

confidence: 99%

Morphological population balance for modeling crystal growth in face directions

2007

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in Wiley InterScience (www.interscience.wiley.com).A morphological (or polyhedral) population balance (PB) model is presented for modeling the dynamic size evolution of crystals grown from solution in all crystal growth directions. The morphological PB approach uses the crystal shape information for a single crystal obtained from morphology prediction, or experiment as the initial face locations, as well as face growth rates to predict the shape evolution of the crystal population. For each time instant during the crystallization process, the prediction uses its shape at the previous time moment, and the growth rate for the specific crystal habit plane. The methodology is demonstrated through a study of potash alum (KAl (SO 4 ) 2 Á12H 2 O), for which literature data is available for comparison and validation. The discretization method, method of classes, was used to convert the equations to ordinary differential form with the computational domain being discretized into small meshes. The ordinary differential equations ([1.5 million) were then solved simultaneously using the Runge-Kutta-Fehlbergh 4th/5th-order solver with automatic time-step control. The results obtained clearly demonstrate that the morphological PB model developed can predict crystal growth and surface area of individual habit faces in detail, together with crystal shape and size evolution.

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“…BFDH, GM and EM calculations are based on mathematical theorems and assumptions, which have been extensively presented in related literature (25)(26)(27) and for this reason not presented in much detail here. In short, the BFDH method is a geometrical calculation that generates a habit taking into consideration the crystal lattice and symmetry operators in order to identify the growth faces and their growth rates.…”

Section: In Silico Calculationsmentioning

confidence: 99%

The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

2014

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-PURPOSE. Pyrimethamine, an anti-malarial agent known to exhibit solid state polymorphism, may be purified by means of recrystallization. Recrystallization may alter the solid state chemistry of pharmaceuticals, which may impact the toxicity and/or manufacturability thereof. We evaluated the risks associated with the recrystallization of pyrimethamine. METHODS. Pyrimethamine was recrystallized using several organic solvents. X-ray diffraction, thermal analysis, infra-red spectroscopy, microscopy, flowability -, solubility and dissolution testing as well as computational work were employed to evaluate the recrystallized products. RESULTS. A toxic solvatomorph of pyrimethamine (Pyr-MeOH) was found to be the product from methanol recrystallization. The elucidation of -and the elaboration on the unique characteristics of Pyr-MeOH provides the pharmaceutical industry with several means to identify Pyr-MeOH and to distinguish it from the pharmaceutically preferred anhydrous form (Pyr). Thermal methods of analysis found that the toxicity of PyrMeOH may be reversed by overcoming a desolvation activation energy of 148 kJ/mol. In addition it was found that recrystallization altered the morphology of Pyr. Angle of repose and tapped density determinations identified that the different morphologies of Pyr displayed differences in powder flow and compressibility behaviour and In Silico calculations were successful in rendering morphologies resembling that found experimentally. CONCLUSION. We present a solvatomorph of pyrimethamine and provide several characteristic means to identify this unwanted toxic form and quantified the energy required to overcome its toxicity. In addition we describe that Pyr may present in different morphologies and show how it may impact the manufacturability thereof.

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Theoretical and Experimental Investigations on the Morphology of Pharmaceutical Crystals

Cited by 44 publications

References 21 publications

Conversion of cellulose Iα to Iβ via a high temperature intermediate (I-HT) and other cellulose phase transformations

Conversion of cellulose Iα to Iβ via a high temperature intermediate (I-HT) and other cellulose phase transformations

Morphological population balance for modeling crystal growth in face directions

The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

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