Crystal polymorphism and pseudopolymorphism of ivermectin

Abstract

Objective: The discovery of a family of natural products, the avermectins, was reported from laboratories in the early eighties. The avermectins are disaccharide derivatives of pentacyclic, 16-membered lactones, active against helminths and arthropods in doses as low as 10 μg/kg, far exceeding the potency of their counterparts. They appear to act by interference with invertebrate neurotransmission (Campbell et al., 1980:1134). lvermectin is the 22.23-dihydro derivative of avermectin B₁, a macrocyclic lactone produced by an actinomycete, Streptomyces averrniti/is. Although the primary uses of ivermectin are in veterinary applications to treat parasite infestations in cattle, sheep, swine, horses and dogs, it is also effective in the treatment of river blindness in man. lvermectin is described as a mixture consisting of 2 homologues a and b. The empirical formulas and molecular weights of the two compounds are C₄₈H₇₄O₁₄, MW = 875.10 and C₄₇H₇₂O₁₄, MW = 861.07, respectively (Fink, 1988:156). Although ivermectin contains two sugar rings and two polar hydroxyl groups, it is nevertheless practically insoluble in water with an Its aqueous solubility at room temperatures is in the order of ≤ 1 μg/ml. Poor aqueous solubility is not contrasted by a general lipophilic solubility, but it does dissolve (>20% w/v) in other protic solvents such as 1- hexanol and methanol. In the absence of extraneous reactants and impurities, ivermectin is a stable molecule in its crystalline powdered state. The optimum pH for solution stability is 6.3. Stability decreases as the pH reaches extreme low or high values. This study concentrated on the preparation of different polymorphs and pseudopolymorphs of ivermectin with different physical properties of which solubility is the most important. Thus, through recrystallisation, it has been attempted to prepare a better soluble and more stable form of ivermectin. Methods: lvermectin was recrystallised from several organic solvents. These products were designated MG1 up to MG 11. The products of crystallisation were characterised by thermal analysis (DSC and TGA), X-ray powder diffractometry (XRPD) and infrared spectroscopy (IR). Solubility, dissolution, and the water-octanol solubility were measured for all the products of recrystallisation. Results: XRD, DSC and TGA analysis of the products of recrystallisation revealed the existence of several crystal forms with distinct XRPD patterns. From methanol (MG 8(1)) and ethyl acetate (MG 7), non­crystalline amorphous powders were obtained. The crystals from acetone (MG 2) were the most soluble and from tetrahydrofuran (MG 11) the least soluble in water. The dissolution behaviour of all the recrystallised products except those crystallised from ethylacetate, propan-2-ol and formed on the bottom of the crystallisation dish of a methanol solution, were similar. After 60 minutes more than 80% of all the crystals except the ethylacetate (50%) product were dissolved. The crystals obtained from propan-2ol dissolved the best (90.4%) within 60 minutes. From solubility measurements in water-octanol mixtures at both pH 1.2 and 7.3, the solubility in the octanol phase were significantly higher than in the water phase. Comparison between the solubilities of the samples in the aqueous phases at the different pH's revealed that the solubility was significant higher at pH 7.3 for all the samples. A change in pH did not effect the solubility in the octanol phase. Conclusion: Through the method of recrystallisation, it was possible to prepare different polymorphic and pseudopolymorphic forms of ivermectin from eight solvents. Solubility studies, dissolution profiles, and water-octanol solubility tests were performed on all the samples and definite differences existed. For solid dosage form design (tablets or capsules), the dissolution results of this study suggest that the crystal form obtained from propan-2-ol would significantly improve the availability. To increase solubility in aqueous based formulation, the product obtained from acetone might be better suited.