Influence of moisture on the crystal forms of niclosamide obtained from acetone and ethyl acetate

Abstract

ABSTRACTof solvated or hydrated crystal forms, crystals in which the solvent molecules occupy regular positions in the crystal lattice, is widespread among compounds of pharmaceutical interest. 4,5 The behavior of pharmaceutical hydrates in response to changes in environmental conditions can have a significant impact on the development process and dosageform performance. The obvious situation that favors the formation of hydrates is recrystallization, using water as a solvent. However, recrystallization using organic solvents can generate a metastable crystal form, which, when exposed to moisture, absorbs water and changes into a hydrate. The water molecule, because of its small size and multidirectional hydrogen bonding capability, is particularly suited to fill structural voids.6 Pfeiffer et al have described such systems wherein the crystalline form is solvated while in equilibrium with a saturated solution and loses most of its solvent upon drying but retains the 3-dimensional structure of the parent solvate. Pfeiffer further refers to the crystals as "desolvated" crystals and emphasizes the need to differentiate them from a truly unsolvated unique structure like the anhydrate. 7 Stephenson et al introduced the term "isomorphic desolvates" as it accurately defines a desolvate that retains the structure of its parent solvate form. They cited several compounds exhibiting such behavior, some of which include cephalexin, cefaclor, erythromycin A, and spirapril hydrochloride. 8 The purpose of this study was to elucidate the formation of crystal hydrates of niclosamide and to delineate the effect of relative humidity on the crystal forms obtained from acetone and ethyl acetate. Recrystallization of niclosamide was performed in the presence and absence of moisture. Two hydrates and their corresponding anhydrates were isolated. The hydrates obtained by the process of recrystallization from acetone (Form I) and that obtained from ethyl acetate (Form II) were classified based on differences in their dehydration profile, crystal structure, shape, and morphology. Crystals obtained in the absence of moisture were unstable, and when exposed to the laboratory atmosphere transformed to their corresponding hydrates. Differential scanning calorimetry thermograms indicate that Form I changes to an anhydrate at temperatures below 100°C, while Form II dehydrates in a stepwise manner above 140°C. This finding was further confirmed by thermogravimetric analysis. Dehydration of Form II was accompanied by a loss of structural integrity, demonstrating that water molecules play an important role in maintaining its crystal structure. Form I, Form II, and the anhydrate of Form II showed no significant moisture sorption over the entire range of relative humidity. Although the anhydrate of Form I did not show any moisture uptake at low humidity, it converted to the monohydrate at elevated relative humidity (>95%). All forms could be interconverted depending on the solvent and humidity conditions. Niclosamide (5-Chloro-N-(2-chloro-4-nitrop...

Niclosamide methanol solvate and niclosamide hydrate: structure, solvent inclusion mode and implications for properties

“…The relationship between the two niclosamide monohydrates was studied further by a range of methods, which consistently suggest that H A is the kinetically favoured form which readily transforms into H B . (Manek & Kolling, 2004, Tian et al, 2010, van Tonder, Mahlatji, et al, 2004 Physical property measurements reported on the solvates listed above, including solubility, dissolution and thermal properties, revealed a high affinity for water of all these crystal forms. (van Tonder, Mahlatji, et al, 2004, van Tonder, Maleka, et al, 2004 This may have potentially impacted some of the measurements reported, given that, for example, niclosamide tetrahydrofuran solvate crystals are reported to undergo desolvation within minutes of being removed from the mother liquor.…”

“…The structure of monohydrate H A has remained unknown, although its significantly lower dehydration temperature (373 K) suggests that the water-molecule inclusion mode is substantially different from that in H B . The relationship between the two NCL monohydrates has been studied further by a range of methods, which consistently suggest that H A is the kinetically favoured form which readily transforms into H B (Manek & Kolling, 2004;Tian et al, 2010;van Tonder, Mahlatji et al, 2004).…”

Cation–π interactions drive hydrophobic self-assembly and aggregation of niclosamide in water

“…4 The crystalline form in which most drugs exist affects their solidstate characteristics. 5,6 Generally, the way drugs react plays a signicant role on their performance characteristics. NC has been reported to crystallize into two solvate forms: two monohydrates (H A and H B ) and one anhydrous.…”

Recrystallization of Active Pharmaceutical Ingredients

“…If a crystallization process generates a metastable intermediary form, it can absorb water when exposed to moisture and change into a hydrate. Water molecules, because of their small size and multidirectional hydrogen bonding capabilities, are particularly suited to fill structural voids (Manek & Kolling, 2004). If a crystallization system is open to atmospheric conditions, as is likely to be the case with evaporative crystallization, hygroscopic solvents will absorb moisture from the air if present.…”