Polymorphism in Molecular Crystals: Stabilization of a Metastable Form by Conformational Mimicry

Crystal Growth & Design

et al. 2014

Pulmonary inhalation is increasingly being selected as a preferred route for the delivery of both small and large drug macromolecules for the treatment of a range of pathologies. The direct crystallization of micronized powders, in particular, paracetamol, remains difficult, as it requires the ability to work in high solution supersaturations where agglomeration, wall crusting, and heterogeneous nucleation hinder the control of crystal size and crystal size distribution. Polymer additives are recognized to help drive the production of a given polymorph or controlling crystal shape by means of adsorption on the crystal surface. With the aim of exploiting the polymer-control nucleation and growth of crystals for enhanced direct crystallization of micronized powders, batch cooling crystallization of paracetamol in water was carried out in the presence of 0.1−0.8% w/w hydroxypropyl methylcellulose (HPMC). In the presence of polymer, the onset of nucleation was delayed and extended beyond the cooling time of the solution, resulting in an isothermal cooling crystallization and the production of micronized paracetamol with a mean crystal size D 50 , in the range of 15−20 μm and an improved crystal size distribution. Equally, the rate generation of solution cloudiness was reduced by over 3-fold for the highest HPMC concentration tested, with no detectable impact on final product yield. The mechanisms for nucleation delay and growth inhibition by HPMC is unknown; however, a modification of crystal's shape observed upon the addition of HPMC to the solution suggested it might be related to mass transfer limitations and intermolecular hydrogen bonding between the large HPMC and the small drug molecules. This technique can potentially be used for direct crystallization of other micronized drugs.

Section: Introductionmentioning

confidence: 99%

Hydroxypropyl Methylcellulose as a Novel Tool for Isothermal Solution Crystallization of Micronized Paracetamol

Crystal Growth & Design

et al. 2014

“…LGA has two recognized polymorphic forms: the metastable, more soluble and prismatic -form, and the stable, less soluble and needle-like -form [20]. A high-resolution analytical balance (made by Mettler-Toledo) with precision of one ten thousandth was used to weigh the LGA samples for experiment.…”

Section: Methodsmentioning

confidence: 99%

Comparative study on ATR-FTIR calibration models for monitoring solution concentration in cooling crystallization

Zhang

Journal of Crystal Growth

Wang

et al. 2017

Abstract:In this paper calibration model building based on using an ATR-FTIR spectroscopy is investigated for in-situ measurement of the solution concentration during a cooling crystallization process. The cooling crystallization of L-glutamic Acid (LGA) as a case is studied here. It was found that using the metastable zone (MSZ) data for model calibration can contribute to the prediction accuracy, compared to the usage of undersaturated zone (USZ) spectra as traditionally practiced which may lead to undesired bias for prediction of the MSZ concentration. Calibration experiments were made for LGA solution under different concentrations. Four candidate calibration models were established using different zone data for comparison, based on a multivariate partial least-squares (PLS) regression algorithm for the collected spectra together with the corresponding temperature values. Experiments under varied concentrations and operational changes of temperature were conducted. The results indicate that using MSZ spectra for model calibration can give more accurate prediction of the solution concentration during the crystallization process. The primary reason was clarified as spectral nonlinearity for measurement between USZ and MSZ. In addition, an LGA cooling crystallization experiment was performed to verify the sensitivity of these calibration models for monitoring the crystal growth process.

“…The L-GA crystals are known to have two polymorphs (Davey et al, 1997;Kitamura and Ishizu, 2000), the prismatic  and the needle-like  forms. (1)…”

Section: Methodsmentioning

confidence: 99%

On-line measurement of the real size and shape of crystals in stirred tank crystalliser using non-invasive stereo vision imaging

Zhang

Cai

Chemical Engineering Science

et al. 2015

Non-invasive stereo vision imaging technique was applied to monitoring a cooling crystallisation process in a stirred tank for real-time characterisation of the size and shape of needle-like Lglutamic acid (LGA)  polymorphic crystals grown from solution. The instrument consists of two cameras arranged in an optimum angle that take 2D images simultaneously and are synchronised with the lighting system. Each 2D image pair is processed and analysed and then used to reconstruct the 3D shape of the crystal. The needle shaped LGA  form crystal length thus obtained is found to be in good agreement with the result obtained from off-line analysis of crystal samples, and is about three times larger than that estimated using 2D imaging technique. The result demonstrates the advantage of 3D imaging over 2D in measurement of crystal real size and shape.