Habit Modification of the Active Pharmaceutical Ingredient Lovastatin Through a Predictive Solvent Selection Approach

Abstract

An analysis of the important intermolecular interactions of the active pharmaceutical ingredient lovastatin which contribute to the surface chemistry and attachment energy morphology is presented. The analysis is supported by a recent redetermination of the single-crystal structure (orthorhombic space group P2₁2₁2₁) and targets the understanding and potential control of the morphology of lovastatin, which tends to crystallize in a needle-like morphology, where the aspect ratio varies depending on the nature of the solvent. The lattice energy was calculated to be −38.79 kcal mol⁻¹ with a small contribution of −2.73 kcal mol⁻¹ from electrostatic interactions. The lattice structure is significantly stabilized by the hexahydronaphthalene ring of the molecule, which contributes 43.39% of the lattice energy. Synthon analysis shows that the dominant intermolecular interaction within the lattice structure of lovastatin is found to be along the a crystallographic axis, associated with a dispersive stacking interaction due to the close packing of 2 hexahydronaphthalene rings resulting in a total interaction energy of −6.46 kcal mol⁻¹. The attachment energy morphology correlates well with the observed crystal morphology which exhibits a needle-like habit dominated by {0 1 1}, {0 2 0}, {0 0 2}, and {1 0 1} crystal forms. The needle capping faces are found to contain the short stacks of hexahydronaphthalene rings where the strong intermolecular synthon is found to contribute positively to the attachment energy and hence growth at this surface. This dominant intermolecular synthon is concluded to be the major cause of enhanced growth along the crystallographic a axis leading to the formation of a needle-like morphology. A habit modification strategy is discussed which uses recrystallization from apolar solvents to reduce the effective growth rate at the needle-capping surfaces. This is supported through experimental data which shows that crystals obtained from crystallization in hexane and methyl-cyclohexane have significantly reduced aspect ratios in comparison to those grown from the more polar methanol and ethyl acetate solutions. Crystals obtained from nitromethane solutions were also found to have a very large reduction in aspect ratio to a prismatic morphology reflecting this solvent's propensity to interact with hydrophobic surfaces, critically with no polymorph change.

Introduction

Mevinolinic acid or lovastatin belongs to the statin class of drug compounds, one of the most widely prescribed drug classes worldwide for the treatment of hypercholesterolemia. Lovastatin targets and inhibits the enzyme hydroxymethylglutaryl coenzyme A reductase, which plays a key role in initiating the synthesis of cholesterol; hence, lovastatin hinders the biosynthesis pathway of cholesterol. Lovastatin is generally isolated through a chemical synthesis or biosynthesis fermentation route, where the product is then isolated and purified through a recrystallization strategy, generally from alcohol or acetone/water mixes.¹

Lovastatin has been the target of many physicochemical screening studies within the literature due to its importance as an industrial active pharmaceutical ingredient (API). The solid-state physicochemical properties of lovastatin have been studied using thermal analysis methods; the melting point was found to be 445 K and where the crystalline material undergoes amorphization when recrystallized with the preservative butylhydroxyanisole.² The solubility of lovastatin was measured in a number of solvent systems, namely in a series of homologous acetates,³ alcohols,⁴ and also in acetone/water mixtures,⁵ where the solubility is lower in polar solvents due to the hydrophobic nature of the compound. Additionally, the nucleation kinetics of lovastatin have been determined using turbidometric techniques in ethanol, methanol, and acetone solutions, where the mechanism of nucleation was found to be instantaneous in ethanol and acetone and progressive in methanol.⁴

Due to the hydrophobicity of lovastatin, the drug falls into the second class of drug compounds under the Biopharmaceutics Classification System,6, 7 where the drug exhibits high permeability and low solubility, the molecular structure and material descriptors for lovastatin are provided in S1 of the Supplementary Information. As a result, the drug is impacted by poor bioavailability and hence efforts to improve the absorption of the drug have included nanoparticle synthesis and implementation of lipid-based carrier systems.8, 9 Lovastatin also exhibits a needle-like morphology when recrystallized from solution, which can lead to problematic downstream processing issues such as poor particle flow, problematic filtration, and particle breakage.¹⁰

The physicochemical and mechanical properties of crystalline materials can be calculated using molecular modeling tools through atom-atom summation methods which use atomistic forcefields to calculate intermolecular interaction strength and directionality.11, 12, 13, 14, 15, 16, 17 Much progress has been made in this field, particularly when applying these “synthonic engineering” methodologies to organic molecular crystals,18, 19 where particle morphology,20, 21 solvent-surface interactions,²² surface chemistry²³ and excipient-API interactions²⁴ are some of the emerging areas of interest. Nguyen²⁵ et al recently applied a synthonic engineering approach to understand the interfacial stability of the crystallographic faces of ibuprofen and rationalize the various aspect ratio crystals obtained from differing solution environments during crystal growth. Rosbottom²⁶ et al have also used synthonic engineering by applying a grid-based surface searching methodology27, 28, 29 to explain the anisotropic wettability of the crystal surfaces of ibuprofen.

This article aims at using the approaches of synthonic engineering and molecular modeling discussed above to further understand the bulk crystal chemistry and surface chemistry of lovastatin in relation to its observed needle-like morphology. Additionally, it aims at quantifying the extrinsic (surface-terminated) synthon contribution to the attachment of molecules at the growing crystal surfaces. This is part of an overall strategy to effect the habit modification of this material to mitigate the impact of the observed needle-like morphology of lovastatin by providing a fundamental molecular understanding of both the crystallographic structure and the nature of the interactions of the solute with its surrounding solution environment.