Effect of Structurally Similar Additives on Crystal Habit of Organic Molecular Crystals at Low Supersaturation

Abstract

Foreign molecules such as additives or impurities may influence crystal morphology to a significant extent by disrupting the growth mechanism and inhibiting the growth rate of certain crystal faces. The additives can be byproducts of a preceding reaction step, or they could be specially designed to obtain specific crystal morphologies for particular applications. Because of the specific chemical structure of structurally similar additives, they can incorporate or lock into the original lattice only in certain configurations; hence, only some of the crystal faces are able to recognize these additive molecules. Once attached, they interfere with the first turn of a rotating growth spiral and hence slow down the growth rate of the face. In this article, we develop a generic probabilistic scheme for quantitatively estimating imposter recognition on each crystal face using a combination of mean field theory and configurational energy minimization. On the basis of this recognition, the mechanistic effect of an impurity on the first turn of the spiral and hence the modified growth rates and modified crystal habits are computed. These concepts are generalized for all molecular crystals, including non-centrosymmetric molecules. We demonstrate the applicability of the model by correctly predicting the experimental morphologies of α-glycine with l-alanine impurity and paracetamol with p-acetoxyacetanilide impurity grown from water.

Influences of Crystal Anisotropy in Pharmaceutical Process Development

“…Chernov ( 47 ), Cabrera ( 109 ), and Vermilyea ( 110 ) have extensively studied the influence of impurities on the development of surface dislocations on crystals and therefore crystal growth. Those studies set the groundwork for the development of a mechanistic framework ( 111 , 112 ) for the prediction of the influence of additives in crystal growth in the context of the infamous BCF model, mentioned earlier. It has been shown that additives posing similar structure with the molecules of the crystal can be used as effective crystal habit modifiers.…”

A design aid for crystal growth engineering

“…The effect of external species such as structurally similar additives has been studied within the context of the mechanistic model [115]; however at present the ability to account for such effects has yet to be built into ADDICT.…”

Influence of emulsion types on nucleation kinetics and growth habit in the cooling crystallization

“…Therefore, many attempts have been made to control those properties through the crystallization techniques. In the crystallization process, crystal size and shape are intimately related with nucleation and crystal growth kinetics . For example, final crystal size is strongly influenced by the population density of crystallizing body that is commonly induced by nucleation.…”

“…Growth kinetics of crystal faces is remarkably affected by structure and composition of chemicals surrounding a crystal due to their anisotropic nature. Therefore, crystal shape can be controlled by solvent or supersaturation control, and addition of tailor‐made additives, because the area of a crystal face is inversely proportional to growth rate of that face .…”