A new high-pressure benzocaine polymorph — towards understanding the molecular aggregation in crystals of an important active pharmaceutical ingredient (API)

Abstract

Benzocaine (BZC), an efficient and highly permeable anaesthetic and an active pharmaceutical ingredient of many commercially available drugs, was studied under high pressure up to 0.78 GPa. As a result, new BZC polymorph (IV) was discovered. The crystallization of polymorph (IV) can be initiated by heating crystals of polymorph (I) at a pressure of at least 0.45 GPa or by their compression to 0.60 GPa. However, no phase transition from polymorph (I) to (IV) was observed. Although polymorph (IV) exhibits the same main aggregation motif as in previously reported BZC polymorphs (I)–(III), i.e. a hydrogen-bonded ribbon, its molecular packing and hydrogen-bonding pattern differ considerably. The N—H...N hydrogen bonds joining parallel BZC ribbons in crystals at ambient pressure are eliminated in polymorph (IV), and BZC ribbons become positioned at an angle of about 80°. Unfortunately, crystals of polymorph (IV) were not preserved on pressure release, and depending on the decompression protocol they transformed into polymorph (II) or (I).

Minimizing Polymorphic Risk through Cooperative Computational and Experimental Exploration

“…Similarly, these chains run parallel to the a -axis for IPN-II and only a modest reduction of this axis is recorded after compression in the DAC (Table S1). This is in line with previous studies that the shortest contacts remain unchanged and transformations instead rely on a rearrangement of longer contacts. , …”

“…This is in line with previous studies that the shortest contacts remain unchanged and transformations instead rely on a rearrangement of longer contacts. 84 , 85 …”

“…This is in line with previous studies that the shortest contacts remain unchanged and transformations instead rely on a rearrangement of longer contacts. 84,85 Accordingly, there are some subtle differences between forms in the interactions of the pyridyl groups in adjacent Hbonding chains. All IPN forms exhibit a short contact between the pyridyl groups via a (pyridyl)C−H•••N(pyridyl) interaction.…”

Minimizing Polymorphic Risk Through Cooperative Computational and Experimental Exploration

“…This is in line with previous studies that the shortest contacts remain unchanged and transformations instead rely on a rearrangement of longer contacts. 82,83 Accordingly, there are some subtle differences between forms in the interactions of the pyridyl groups in adjacent H-bonding chains. All IPN forms exhibit a short contact between the pyridyl groups via a (pyridyl)C-H•••N(pyridyl) interaction.…”

Hydrate vs Anhydrate under a Pressure-(De)stabilizing Effect of the Presence of Water in Solid Forms of Sulfamethoxazole

“…However, it is worth noting that during the tableting process via compaction of APIs can also be subjected to nonambient pressure, a stimulus known to efficiently affect the crystal structure. Exposing crystals to high pressure can lead to solid-state phase transitions, , crystal amorphization, chemical reactions in the solid state, or even pressure-induced solvation. , In rare cases pressure has even led to an increase in the solubility of the investigated crystals. , Therefore, pressure can be a powerful tool used in the search of new crystal forms of the APIs, but it also should be considered in the study of their stability to avoid unintentional solid-state transformations during the tablet manufacturing process. , Similarly to the solubility, the pressure stability of a drug substance can be modified (increased or decreased) by introducing foreign molecules or ions into the crystal structure and formation of multicomponent crystals . The destabilizing effect of a second component was observed for glycine and its cocrystal with glutaric acid, as well as for dl -alanine and dl -alaninium semioxalate monohydrate, where the introduction of the second component led to the disruption of homosynthones.…”