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44172-AC10
Next Generation Models for Predicting the Shape of Solution-Grown Organic Crystals in the Presence of an Additive
Our research deals with the use of tailor-made additives as growth inhibitors for manipulating the shape of organic crystals. The most problematic shapes for many crystal growers are needles and flakes. We have focused our attention on needles because they are commonly encountered in pharmaceutical manufacturing. We have performed experiments on “typical” needle-forming molecules and we are developing models for predicting how tailor-made additives modify crystal shape. The goal is to perform many “computer experiments” quickly so as to select candidate additives that have the potential to disrupt needle formation, thereby creating a rational experimental design.
We searched the literature for details of needle crystals whose aspect ratios were not less than 50:1:1 (with 100:1:1 being preferred). Our search was constrained by two requirements: (1) the crystal molecule should be organic (free-base), and (2) the crystal structure should have been solved. During the course of our investigation, we recognized that there seems to be two equivalence classes of molecules that crystallize as needles. One class, which we term absolute, exhibits needle morphology regardless of the solution environment. The other class, which we term conditional, exhibits needle morphology only in certain solvents. Since absolute needles cannot be avoided by changing solvent, other strategies must be employed, and the one we have chosen to investigate is the use of tailor-made additives. We selected the alpha polymorph of p-aminobenzoic acid (PABA) and 2-hydroxybenzoic acid (salicylic acid) as the two model solutes – both grow as needles. The former is an absolute needle system, the latter is conditional. PABA is known to grow as needles from every solvent tried, including ethanol, water, and ethyl acetate. The crystal shape of PABA grown from water is shown in the left hand figure of the nugget. Salicylic acid, on the other hand, grows as a needle from acetone and ethanol, but not from water from which it grows as a cube.
One set of experiments performed tested the efficacy of the tailor-made additive 4-propylbenzoic acid (4pBA) in the disruption of needle growth of PABA. In the first set of experiments, we prepared a solution of 2.5 g PABA, a mixture of 25 mL of water and 25 mL of ethanol, and 0.25 g of 4-propylbenzoic acid. This solution was transferred to another petri dish and the solvent was allowed to evaporate. In this dish, however, no needles were observed to form. The crystal shapes could be characterized as ``rod-like,'' meaning they possess aspect ratios on the order of 15:1, as can be seen in the right hand figure in the nugget. Many other experiments, under varying conditions, confirm that 4pBA is effective at drastically reducing the aspect ratio of the PABA needles.
Our experimental results demonstrate that PABA consistently exhibits needle morphology in solutions with ethanol, ethyl acetate, water, and a mixture of water and ethanol. Together with other literature data we believe this growth behavior to be characteristic of PABA grown out of any other solvent in which it is soluble, i.e., it is an absolute needle. In contrast, salicylic acid shows a drastically different habit when grown from water rather than ethanol.
We propose that absolute needles are caused by the intrinsic packing of the molecules in three dimensions; therefore, the task is to find the characteristics of the crystallographic faces that intersect the needle direction which would, independent of the solvent environment, offer virtually no resistance (or at least, the same low resistance) to the incorporation of nutrient at the surface. We further propose that the additive disrupts growth in this needle direction, causing the face to slow down and become much larger on the final crystal form. Currently, we are developing growth models that account correctly for these effects which can be used to predict the effects of both solvent and additive on crystal shape.
