New form discovery for the analgesics flurbiprofen and sulindac facilitated by polymer‐induced heteronucleation

Abstract

The selection and discovery of new crystalline forms is a longstanding issue in solid-state chemistry of critical importance because of the effect molecular packing arrangement exerts on materials properties. Polymer-induced heteronucleation has recently been developed as a powerful approach to discover and control the production of crystal modifications based on the insoluble polymer heteronucleant added to the crystallization solution. The selective nucleation and discovery of new crystal forms of the well-studied pharmaceuticals flurbiprofen (FBP) and sulindac (SUL) has been achieved utilizing this approach. For the first time, FBP form III was produced in bulk quantities and its crystal structure was also determined. Furthermore, a novel 3:2 FBP:H 2 O phase was discovered that nucleates selectively from only a few polymers. Crystallization of SUL in the presence of insoluble polymers facilitated the growth of form I single crystals suitable for structure determination. Additionally, a new SUL polymorph (form IV) was discovered by this method. The crystal forms of FBP and SUL are characterized by Raman and FTIR spectroscopies, X-ray diffraction, and differential scanning calorimetry.

Polymorphism and Solvatomorphism 2007

“…Nucleation onto polymer surfaces represents another route for the discovery of new polymorphs, and studies have been conducted where flurbiprofen and sulindac were crystallized in the presence of a number of commercially available polymers 50. The use of this methodology enabled the bulk production of flurbiprofen Form‐III in bulk quantities, isolation of a 3:2 flurbiprofen hydrate species that could only be obtained through polymer‐induced heteronucleation, crystallographic‐quality sulindac Form‐I, and a previously unreported sulindac Form‐IV.…”

Understanding Pharmaceutical Polymorphic Transformations II: Crystallization Variables and Influence on Dosage Forms

“…Several hydrophilic adjuvants of herbal, animal, microbial or synthetic origin have been reported for their ability to modify crystal habit [26][27][28][29][30], stabilize metastable [31][32][33] and amorphous form [34][35][36], and selectively screen polymorphic forms [37][38][39][40][41][42].…”

Enhanced Drug Delivery by Dissolution of Amorphous Drug Encapsulated in a Water Unstable Metal–Organic Framework (MOF)

“…The drug@MOF‐5 composites exhibit decomposition behavior akin to pure MOF‐5 (see Figure S5–S7, Supporting Information). Notably, SUL@MOF‐5 decomposition in SG media resulted in SUL crystallized as form I (monoclinic) polymorph rather than as the more stable form II (orthorhombic); this finding is in accord with the Ostwald step rule …”

“…Sulindac is a poorly water‐soluble weak acid with pH‐dependent solubility which exhibits a very low solubility in SG media . It is important to note that during dissolution of SUL@MOF‐5 and SUL/MOF‐5 PM in SG media, the pH slightly increases due to MOF‐5 decomposition products.…”