435128 Controlling Crystal Size, Shape and Purity during Crystallization By Using Additives

Monday, November 9, 2015: 5:20 PM
Salon J (Salt Lake Marriott Downtown at City Creek)
Akos Borsos, Chemical Engineering Department, Loughborough University, Loughborough, United Kingdom and Zoltan K. Nagy, School of Chemical Engineering, Purdue University, West Lafayette, IN

Crystallization which is a purification and separation unit operation plays an important role in the industrial production of pharmaceuticals. The properties of the produced crystals such as purity or size and shape distribution have strong impact on the downstream processes as well as on the end usage. It is known, that chemicals are generally contaminated by different amounts of impurities, which can come from different sources, such as from upstream processes or chemical side reactions [1]. In most of the industrial processes, the effect of impurities may result e.g. in needle shape crystals which impeding manufacturability of the solid dosage form. While crystallization is often used as a purification process, trace amount of impurities generally exist in the product. While in some cases impurities of various amounts are acceptable for certain highly toxic impurities the acceptable limits are very low and difficult to achieve using a single crystallization step. For example genotoxic impurities carry significant health risk and strict regulations are applied on the concentration of these materials  [6,8,9]. Impurities, even if it is in trace amounts, can influence the crystal properties like crystal shape. In this case, impurities are called as crystal growth modifiers (CGMs) [2-6]. In this work, a method is presented, which reduces the possible undesired effect of the CGMs during crystallization by using a control additive (CA). The control method is based on a chemical reaction between the control additive and the growth modifier, which results in a non-adsorptive reaction product.  Thus, the concentration of CGM in the solution and thus in the solid phase is the function of the additive concentration in the solution. It is also known that the concentration of the CGMs in the solution affects the rate of the change of crystal growth.

This work deals with the investigation and control of batch cooling crystallization in the presence of crystal growth modifiers. The objectives of the control method are to maintain the purity of the crystal product and also to control the crystal size and shape distribution. A mathematical model including nucleation and growth of two characteristic crystal sizes as well as impurity adsorption and chemical reaction model is developed in order to investigate and control the purity and the crystal shape. The growth modifiers influence directly the growth kinetics. This inhibitory effect on the crystal surfaces leads to changed crystal size and shape distribution [2-6]. On the other hand, growth modifiers are built in the crystal structure according to surface adsorption mechanism and so CGMs also change the purity of the crystal product [7]. The proposed purity control method is based on chemical reaction between the undesired impurity and the control additives which provides an alternative transformation route for the compound against the surface adsorption.  Hence, the chemical reaction inhibits the adsorption rate by lowering the concentration in the solution.   

Utilizing the benefits of the competitive adsorption and reaction mechanisms, model based control for crystal shape and purity is developed. The simulator is suitable to calculate the optimal concentration of control additive in order to achieve desired crystal shape and/or reducing the impurity concentration below the desired limits. The results demonstrate the efficiency of the proposed approach for shape and purity control.

Acknowledgement: Financial support provided by the European Research Council grant no.[280106-CrySys] is acknowledged.


[1] N., Variankaval, A.S., Cote, M.F., Docherty, 2008. From form to function: Crystallization of active pharmaceutical ingredients. AIChE Journal, 54(7), 1682-1688.

[2] A., Majumder, Z.K., Nagy, 2013. Prediction and control of crystal shape distribution in the presence of crystal growth modifiers. Chemical Engineering Science, 101, 598-602.

[3] R.J., Davey, 1976. The effect of impurity adsorption ion the kinetics of crystal growth from solution. Journal of Crystal Growth, 34, 109-119.

[4] N., Kubota, J.W., Mullin, 1995. A kinetic model for crystal growth from aqueous solution in the presence of impurity. Journal of Crystal Growth, 152(3), 203-208.

[5] N., Kubota, S., Sasaki, N., Doki, N., Minamikawa, M., Yokota, 2004. Absorption of an Al(III) impurity onto the (100) face of a growing KDP crystal in supersaturated solution. Crystal Growth and Design, 4(3), 533-537.

[6] A., Borsos, A., Majumder, Z. K., Nagy, 2014. Model development and experimental validation for crystal shape control by using tailored mixtures of growth modifiers. Computer Aided Chemical Engineering, 33, 781-786.

[7] K., Maeda, R., Tabuchi, Y., Asakuma, K., Fukui, 2006. Distribution of metallic ions in single KDP crystal grown from aqueous solution. Cryst. Res. Technol., 41(10), 955-960.

[8] A., Garcia-Arieta, 214. Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence. European Journal of Pharmaceutical Sciences, 65, 89-97.

[9] S., Gorog, 2006. The importance and the challenges of impurity profiling in modern pharmaceutical analysis. Trends in Analytical Chemistry, 25 (8), 755-757.

Extended Abstract: File Not Uploaded
See more of this Session: PAT for Crystallization Development and Manufacturing
See more of this Group/Topical: Process Development Division