Idoudi Sourour, Saleh Alaaeldin, Akkbik Mohammed, Amine Leena, Alansari Khalid, Rachid Ousama, Alkilany Alaaldin M
Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, Doha P.O. Box 2713, Qatar.
College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar.
Pharmaceutics. 2024 Nov 22;16(12):1502. doi: 10.3390/pharmaceutics16121502.
Ketamine HCl, an FDA-approved therapeutic, is administered through various routes, including intranasal delivery. Administering an adequate therapeutic dose of intranasal ketamine HCl is challenging due to the limited volume that can be delivered intranasally given the current commercially available concentrations. This study investigates solubilizing strategies to enhance the aqueous solubility of ketamine HCl for intranasal administration. We assessed the solubility profile of ketamine HCl by evaluating factors such as pH, co-solvents, and surfactants. Additionally, we developed and validated a UV-Vis spectroscopy method for ketamine HCl analysis. Our solubility screening in various organic co-solvents revealed the following order of effectiveness in enhancing solubility: methanol > water > propylene glycol > ethanol > dimethyl sulfoxide (DMSO) > N-methyl-2-pyrrolidone (NMP). Despite methanol's superior solubility, its potential toxicity, coupled with the relatively lower effectiveness of other solvents compared to water, suggests that a co-solvency approach is not advantageous for ketamine HCl. We found that ketamine HCl solubility increased with medium acidity, with pH 3.5 being the optimal for further formulation studies. The impact of pharmaceutical surfactants on ketamine HCl solubility at an acidic pH was also evaluated. Surfactants tested included SDS, PEG 400, PVP, Tween 20, poloxamer 188, and lecithin. Notably, PEG 400 and PVP reduced solubility due to a salting-out effect, whereas Tween 80, lecithin, and poloxamer 188 slightly improved solubility through micelle formation. Among the surfactants tested, 1% SDS emerged as the most effective in enhancing ketamine HCl solubility. These outcomes highlight the potential of these solubilization strategies to address the solubility limitations of ketamine HCl, enabling the preparation of highly concentrated ketamine HCl formulations for intranasal delivery.
盐酸氯胺酮是一种经美国食品药品监督管理局（FDA）批准的治疗药物，可通过多种途径给药，包括鼻腔给药。由于目前市售浓度下鼻腔内可输送的体积有限，给予足够治疗剂量的鼻腔内盐酸氯胺酮具有挑战性。本研究调查了增溶策略，以提高盐酸氯胺酮在鼻腔给药时的水溶性。我们通过评估pH值、助溶剂和表面活性剂等因素来评估盐酸氯胺酮的溶解度曲线。此外，我们开发并验证了一种用于盐酸氯胺酮分析的紫外可见光谱法。我们在各种有机助溶剂中的溶解度筛选揭示了在提高溶解度方面的有效性顺序如下：甲醇>水>丙二醇>乙醇>二甲基亚砜（DMSO）>N-甲基-2-吡咯烷酮（NMP）。尽管甲醇的溶解度优越，但其潜在毒性，再加上与水相比其他溶剂的效果相对较低，表明助溶方法对盐酸氯胺酮并不有利。我们发现盐酸氯胺酮的溶解度随介质酸度增加而增加，pH 3.5是进一步制剂研究的最佳值。还评估了药用表面活性剂在酸性pH值下对盐酸氯胺酮溶解度的影响。测试的表面活性剂包括十二烷基硫酸钠（SDS）、聚乙二醇400（PEG 400）、聚乙烯吡咯烷酮（PVP）、吐温20、泊洛沙姆188和卵磷脂。值得注意的是，PEG 400和PVP由于盐析效应而降低了溶解度，而吐温80、卵磷脂和泊洛沙姆188通过形成胶束略微提高了溶解度。在所测试的表面活性剂中，1%的SDS在提高盐酸氯胺酮溶解度方面最为有效。这些结果突出了这些增溶策略解决盐酸氯胺酮溶解度限制的潜力，从而能够制备用于鼻腔给药的高浓度盐酸氯胺酮制剂。
