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Crystengcomm CrystEngComm PAPER Thermodynamics and preliminary pharmaceutical characterization of a melatonin–pimelic acid Cite this: CrystEngComm,2015,17, 612 cocrystal prepared by a melt crystallization method† Yan Yan,ab Jia-Mei Chen*a and Tong-Bu Luab Pharmaceutical cocrystals have been extensively investigated as a promising approach to improve drugs' physicochemical properties. Cocrystals are usually prepared using solution-mediated methods and grinding methods. In this study, a cocrystal of pimelic acid with poorly soluble melatonin was produced using a melt crystallization method by controlling the crystallization within a specific temperature range. The cocrystal was characterized by infrared spectroscopy, powder and single crystal X-ray diffraction. The binary phase diagram and the formation enthalpy established by differential scanning calorimetry provided the rationale Received 18th September 2014, for this spontaneous cocrystallization system. The cocrystal exhibited higher apparent solubility, a faster Accepted 1st November 2014 dissolution rate and acceptable stability as compared to the original melatonin. The study has shown that the melt crystallization method can be considered as a competitive route for producing pharmaceutical DOI: 10.1039/c4ce01921k cocrystals with improved properties and the thermodynamic investigation can provide in depth under- www.rsc.org/crystengcomm standing and guidance on the melt crystallization of cocrystals. the growing number of research publications and patent Introduction – applications.4 12 Pharmaceutical cocrystals can be defined as crystalline Cocrystals are usually prepared using solution- materials composed of an active pharmaceutical ingredient mediated methods (including solvent evaporation, reaction – (API) and one or more pharmaceutically acceptable com- crystallization, slurrying, anti-solvent addition, etc.).13 17 This pounds (guests, coformers), usually held together by reliable approach, however, is limited by the time-consuming solvent – hydrogen bonding interactions, in the same crystal lattice.1 3 selection process, the potential for single component crystal- The molecular packing rearrangements of APIs in cocrystals lization and solvate formation. Solid-based methods (neat or are facilitated by the introduction of guest molecules into the solvent-assisted grinding) have also been demonstrated as crystal lattice, resulting in the modification of their relevant effective methodologies for the preparation of cocrystals.13,18 physicochemical properties. Thus, pharmaceutical cocrystals Grinding methods often need special equipment to keep the provide new opportunities to enhance the physicochemical grinding frequency, and the resulting products often contain properties, such as the melting point, hygroscopicity, mechani- amorphous impurities. Additionally, thermal methods cal properties, permeability, solubility, dissolution rate, and bio- (Kofler's technique, co-melting or melt crystallization), which – availability, of APIs.4 11 In addition, the formation of cocrystals have long been known but rarely used in cocrystal systems, may also create the intellectual property and new patents of are a green alternative approach for identifying cocrystal – APIs, and thus extend their life cycle in the pharmaceutical phases.19 22 This approach could only be applied to thermally industry.12 Hence, pharmaceutical cocrystals have drawn great stable compounds with appropriate melting points. The attention from both academia and industry as evidenced by choice of cocrystallization techniques in cocrystal screening depends on the specific properties of the starting materials, including solubility, crystallinity, melting point, thermal stability, etc. a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. Melatonin (MT, Fig. 1) IJN-acetyl-5-methoxytryptamine), a E-mail: [email protected]; Fax: +86 20 84112921; natural product, is found in the pineal gland and excreted as Tel: +86 20 84112921 a hormone in humans.23 It is produced in the brain to help b MOE Key Laboratory of Bioinorganic and Synthetic Chemistry/School of regulate the sleep and wake cycle.24 Exogenous MT is used Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China † CCDC 1024880. For crystallographic data in CIF or other electronic format see orally for jet lag, insomnia, shift work disorder, circadian DOI: 10.1039/c4ce01921k rhythm disorders in blind individuals, and benzodiazepine 612 | CrystEngComm, 2015, 17,612–620 This journal is © The Royal Society of Chemistry 2015 CrystEngComm Paper Table 1 The results of melt crystallization screen experiments with dif- ferent coformers Coformer MPa/°C Screen resultsb Glycolic acid 80 × Glutaric acid 98 × Oxalic acid 99 × Pimelic acid 103 √ Mandelic acid 119 × Fig. 1 The structures of (a) MT and (b) PA. Benzoic acid 121 × Malic acid 131 × Cinnamic acid 134 × 25 and nicotine withdrawal. In most countries MT prepara- a b √ × 26 Melting point. : formation of a new crystalline phase. : the tions are available as food supplements. A prescription-only physical mixture of MT and each coformer. MT product was approved for use by the European Medicines Agency in 2007.27 MT belongs to Class II of the Bio- pharmaceutics Classification System (BCS) with low solubility Hot-stage microscopy (HSM) 28,29 and high permeability. The oral bioavailability of MT in Thermomicroscopic investigations were performed with an 30 humans is limited and variable. Consequently, improving optical polarizing microscope (Nikon LV100 POL) equipped the solubility of MT is highly desirable. with a Linkam hot stage THMS 600 connected to a THMS Herein we attempted to address the deficiency in solu- 600 temperature controller and an LNP 95 liquid nitrogen bility of MT by cocrystallization with soluble guest mole- pump. The microscopy images were recorded with a CCD cules. Formation of a cocrystal requires complementary camera attached to the Nikon LV100 POL microscope at every hydrogen bonding between MT and a second molecule. The 10 s time interval using the Linksys 32 image capture soft- most useful hydrogen bonding group of MT is the second- ware. A 1 : 1 MT/PA physical mixture was heated to 130 °C, ary amide functionality, which is known to form robust and the temperature was kept until all the solids completely − hydrogen bonding interactions with carboxylic com- melted. Then the melt was cooled to 50 °Catarateof10°Cmin1 31,32 pounds. A group of nontoxic carboxylic acids were used and the temperature was kept at 50 °C until the crystalliza- for cocrystal screening. Finally, only one cocrystal of MT tion process was completed. with pimelic acid (PA, Fig. 1) was successfully obtained through a melt crystallization method and characterized Preparation of single crystals of the MT–PA cocrystal by infrared spectroscopy, powder and single crystal X-ray diffraction. Thermodynamic investigation and pharmaceuti- The products obtained by melt crystallization were used as cal characterization of the MT–PA cocrystal were also raw materials for growing high-quality crystals from solution. – carried out. The powder (20 mg) of the MT PA cocrystal was dissolved in a mixed solvent of dichloromethane (1 mL) and n-hexane (0.6 mL). The resulting solution was allowed to evaporate Materials and methods slowly at room temperature and needle-like single crystals Materials were obtained. MT was purchased from Hubei Yuancheng Pharmaceutical Single crystal X-ray diffraction Co., Ltd. All of the coformers were purchased from Aladdin Reagents Inc. All other chemicals and solvents were commer- Single crystal X-ray diffraction data for the MT–PA cocrystal cially available and used as received. were collected on an Agilent Technologies Gemini A Ultra system with graphite monochromated Cu Kα radiation Melt crystallization Table 2 The results of melt crystallization experiments at different MT/PA A melt crystallization method was employed to screen a total molar ratios and different holding temperatures after cooling the melt of 8 carboxylic acids and determine whether unique b cocrystalline phases with MT were able to form. In a typical Results a experiment, a physical mixture of MT and each coformer at a Temperature 2 : 1 MT/PA 1 : 1 MT/PA 1 : 2 MT/PA − chosen ratio was heated at 10 °C min 1 until a melt was RT Mixture Mixture Mixture formed. The molten mixture was then cooled to different spe- 30 °C Mixture Mixture Mixture − ° cific temperatures at a cooling rate of 10 °C min 1. Then the 40 C Mixture Mixture Mixture 50 °C Cocrystal + MT Cocrystal Cocrystal + PA mixture was kept at each temperature until the crystallization 60 °C Cocrystal + MT Cocrystal Cocrystal + PA process was completed, which usually takes 10 to 24 h. The 70 °C Cocrystal + MT Cocrystal Cocrystal + PA resulting solids were analyzed by X-ray diffraction for new 80 °C Molten Molten Molten crystalline phases. The results of the screen experiments are a Room temperature (~25 °C). b Mixture: physical mixture of MT listed in Tables 1 and 2. and PA. This journal is © The Royal Society of Chemistry 2015 CrystEngComm,2015,17,612–620 | 613 Paper CrystEngComm (λ = 1.54178 Å). Cell refinement and data reduction were Table 4 Hydrogen bond parameters for the MT–PA cocrystal applied using the program of CrysAlisPro.33 The structures D–H⋯AD⋯A (Å) D–H⋯A(°) were solved by direct methods using the SHELX-97 program34 – ⋯ and refined by the full-matrix least-squares method on F2. All O3 H3 O1 2.575(2) 164(4) O6–H6⋯O5a 2.660(2) 172(3) non-hydrogen
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