Improving hygroscopic stability of palmatine chloride by forming a pharmaceutical salt cocrystal of palmatine chloride-gallic acid with neutral molecule
Graphical abstract
Introduction
The hygroscopicity of drugs is one of the important factors affecting the storage and transportation of solid pharmaceutical formulations [1]. Therefore, the increase of hygroscopicity of solid pharmaceutical formulations will easily lead to poor dispersion, decreased fluidity, enhanced viscosity and agglomeration of solid pharmaceutical formulations, causing great difficulties in the subsequent preservation of solid pharmaceutical formulations [2]. At the same time, it may cause unpredictable chemical changes such as hydrolysis and oxidation of solid pharmaceutical formulations, which may reduce the safety and effectiveness of solid pharmaceutical preparations and seriously affect the clinical application of drugs. At present, the main methods to improve the hygroscopic stability of solid pharmaceutical formulations are film coating, adding pharmaceutical excipients and freeze-drying technology [1]. However, although these methods could improve the hygroscopic stability of active pharmaceutical ingredients (APIs), most of them may lead to other difficulties that are difficult to solve. For instance, film coating and adding pharmaceutical excipients can improve the hygroscopic stability of active pharmaceutical ingredients, but the disadvantages of complex operation and high cost may limit the development of solid pharmaceutical formulations [[3], [4], [5]]. Although freeze-drying technology can improve the hygroscopic stability of APIs, the development of solid pharmaceutical formulations is limited due to its complex process, long time-consuming and sometimes need to add freeze-drying protectants to prevent solid pharmaceutical formulations [[6], [7], [8], [9]]. In past years, conversely, the emerging pharmaceutical cocrystal technology can improve the physicochemical properties of APIs. And the pharmaceutical cocrystal has excellent stability owing to its fixed arrangement [[10], [11], [12], [13]]. Therefore, it is a challenging problem to obtain pure substances with the certain stoichiometric ratio in a simple method to improve the hygroscopic stability of APIs.
Palmatine (Scheme 1) which belongs to alkaloid that occurs widely in the plant kingdom and as a promising and nonnegligible API, is of scientific interest due to its antidepressant, pain relief, sedation, hypnosis, anti-inflammatory, antifungal and antibacterial properties [[14], [15], [16]]. Palmatine chloride (PMTCl) is most commonly used in commercial palmatine tablets. However, chloride anions, as a negatively charged anion, which can combine with external water molecules through hydrogen bonds, its hygroscopic stability becomes worse because of the presence of chloride anions, and it is easy to agglomerate and deliquesce after being humidified in the air, affecting its transportation, storage and clinical medicinal effect [[17], [18], [19]]. Therefore, improving the hygroscopic stability of PMTCl has become one of the primary factors for the better storage and clinical medicinal effect of PMTCl. Lately, it was reported that berberine chloride which is similar to palmatine chloride in chemical structure can form a salt cocrystal with better hygroscopic stability by introducing neutral molecules [20,21]. Therefore, we envisage that it is possible to prepare a salt cocrystal of PMTCl similar to berberine chloride by introducing neutral molecules, which will hopefully ameliorate the hygroscopic stability of PMTCl, and further improve its storage and clinical medicinal effect.
Based on the above-mentioned conjecture, with the aim to improve the hygroscopicity of PMTCl, it is necessary to prepare the single crystal of pharmaceutical salt cocrystals. On the basis of summarizing the past experience of our research group in the synthesis of pharmaceutical salt/cocrystals, the formation of pharmaceutical cocrystals was found to be caused by the following: the presence of carboxyl, hydroxyl or O heteroatoms in the structure of the coformer makes it easier to form intermolecular hydrogen bonds with active pharmaceutical ingredients [22]. Therefore, there are several reasons that GA neutral molecule were chosen as the pharmaceutical cocrystal former and the design and synthesis of a salt cocrystal of palmatine chloride: (1) Gallic acid are generally regarded as safe (GRAS) reagents grounded by the FDA [23]. (2) The structure of Gallic acid contains carboxyl group that could be used as hydrogen bond receptor and can be connected with PMTCl through hydrogen bond. (3) Gallic acid contains three hydroxyl groups in its structure, which can furnish hydrogen atoms and bind with chloride ions in palmatine chloride by intermolecular hydrogen bond. Based on the above we will explore the following: contents: (1) characterization of the structure of the PMTCl-GA pharmaceutical salt cocrystal. (2) The effect of neutral components in the structure of PMTCl-GA pharmaceutical salt cocrystal will be explored. (3) The internal relationship between the structure of PMTCl-GA and its hygroscopic stability will be explored.
Section snippets
Materials and methods
Palmatine chloride (PMTCl, 98%), Gallic acid (GA, 98%) and solvents were obtained commercially and used without further purification. A Rigaku D/MAX 2500V PC diffractometer was applied and X-ray powder diffraction (XPRD) was recorded using Cu Kα radiation as well as at 30 kV and 40 mA, and each data was collected within the 2θ range of 2–50° at room temperature [24]. Thermogravimetric analysis (TGA) was performed applying a perkin-Elmer TGA7 instrument in a nitrogen atmosphere at a heating rate
Single crystal X-ray diffraction
The structural analysis of PMTCl-GA shows that PMTCl-GA contains four components in the stoichiometric ratio of 2:2:1:2. Its asymmetric unit is composed of two PMT cations, two chloride anions, one gallic acid molecule and two methanol molecules as shown in Fig. 1a. In PMTCl-GA, a new model of synthon R46 (30) was formed by the sequential connection between adjacent asymmetric units via hydrogen bonds O3–H3⋯Cl1, C8–H8⋯Cl1 and C6–H6A···O7, and Fig. 1d zooms the synthon R46 (30) with hydrogen
Conclusion
In this thesis, an unreported salt cocrystal of palmatine chloride with gallic acid (GA)(2(C21H22O4NCl)·C7H6O5·2CH3OH, PMTCl-GA) was synthesized, which can effectively ameliorate the hygroscopic stability of PMTCl by introducing GA neutral molecule and methanol. The structural analysis shows that in the salt cocrystal of PMTCl-GA, chloride anions, the GA neutral molecule, methanol and palmatine cation promote crystal stacking through the formation of hydrogen bonds, thus building a stable
Author statement
I have made contributions to the design of the work, as well as the acquisition, analysis and interpretation of data in this work. Furthermore, I have drafted and revised it carefully. I agree to be accountable for all aspects of the work.
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgement
This work was supported by Joint Guidance Project of Natural Science Foundation of Heilongjiang Province [No. LH2019H059].
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Improving hygroscopic stability of palmatine by replacing Clˉ and preparing single crystal of palmatine-salicylic acid
2022, Journal of Molecular StructureCitation Excerpt :The purity of the crystalline phase was utilized by powder X-ray diffraction (PXRD). The tested results reveal that the patterns of the sample are different from that of PMTCl and SA, indicating new crystalline phases have formed in sample [42]. Moreover, experimental data show that single crystal diffraction data are in good agreement with simulation results (Fig. 1).