(684b) Selective Crystallization of the Metastable Alpha Form of L-Glutamic Acid through Feedback Concentration Control

Polymorphism is the existence of a chemical compound to adopt different crystalline arrangements. Although chemically identical, different polymorphs display a variation in physical properties such as crystal morphology, density, solubility, and color which exert an influence on the performance of the product, for example, the bioavailability and shelf-life of pharmaceutical compounds. With the increasing structural complexity of high value-added products, multiple polymorphs are more frequently encountered in the pharmaceutical industry. It is pertinent to have a consistent and reliable production process for the desired polymorph to achieve feasible economic yield as well as for regulatory compliance. Crystals of the most thermodynamically stable polymorph can be grown as long as sufficient process time is allowed under suitable crystallization conditions like temperature and stirring rate. Growing large crystals of the metastable form is more difficult; the main challenge being to prevent transformation to the most stable polymorph while providing enough time for growth.

This paper shows how to use feedback control to reproducibly and efficiently produce large crystals of a metastable polymorph, using L-glutamic acid as the model system. L-glutamic crystals have two known polymorphs (alpha and beta), which are monotropically related.1 The beta crystals are needle-like platelets, while the alpha crystals have a prismatic morphology or granular morphology if precipitated at low supersaturation.1 In industrial processes, the alpha polymorph is generally preferred because of the ease in subsequent downstream separation processes.2 Numerous previous works have studied the polymorphic transformation behavior of L-glutamic acid.1,3,4,5,6,7 At 45 degrees Celsius or higher, excess amounts of alpha L-glutamic acid in a saturated aqueous solution will transform into the stable beta form; this transformation is solvent-mediated and consists of two steps---the dissolution of the alpha crystals and the re-nucleation and growth of the beta form, which is the rate determining step.1 The transformation has a strong temperature dependence1,5,6 with slower transformation rate at lower temperatures.

Industrial batch crystallization processes are typically designed to follow a temperature or solvent addition profile, which can be determined by models of the nucleation and crystal growth kinetics or by trial-and-error experimentation. The kinetic information can be obtained from a succession of crystallization experiments,8,9,10 but this may prove laborious and time consuming. A different approach, which does not require accurate kinetic data or repetitive trials, is to operate the crystallizer based on the solution concentration measurement so that it follows a supersaturation profile within the metastable zone to avoid unwanted nucleation, which would otherwise widen the crystal product size distribution.11,12,13 This concentration control strategy has been shown to be less sensitive to variations in growth and nucleation kinetics and most practical disturbances for the cooling crystallization of a non-polymorphic system.14 This approach also has been shown to facilitate the rapid development of batch antisolvent crystallization processes.15,16

This paper describes the application of this concentration control methodology to the polymorphic system of L-glutamic acid in water. The objective is to achieve selective crystallization with uniform crystal size of the metastable polymorph for a seeded system. Previous works in selective crystallization of the metastable form utilized different approaches such as identifying a critical level of seed loading necessary to suppress secondary nucleation of both polymorphs17 and fines dissolution18 in the case of glycine, as well as using additives to stabilize the metastable form by conformational mimicry for L-glutamic acid.19 Our control strategy to selectively grow the alpha L-glutamic acid polymorph uses in-situ solution concentration measurement to follow the supersaturation profile setpoint within the metastable zone. It does not necessitate the use of critical amounts of seed loading or additives.

The lower and upper bounds of the operating regime are specified by the alpha form solubility curve and metastable limit, respectively. ATR-FTIR spectroscopy coupled with a calibration model constructed using chemometric techniques20,21,22 was used to provide in-situ solution concentration measurement. Laser backscattering (known commercially as the Lasentec FBRM), which measures in-situ the characteristics of crystal size distribution, was used to detect the metastable limit, as previously demonstrated14,23,24 for the seeded system. The seeded batch cooling crystallizations were implemented with the concentration control approach using different supersaturation profiles to obtain the most appropriate batch crystallization recipe for selectively growing metastable L-glutamic acid crystals.

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