High Throughput Solubility Screening Method for Assessing Feasibility of Developing Self-Emulsifying Lipid Based Formulations
Posted on January 17,2017
By Ad Bernaerts, Martin Piest, Katerina Rousou & Marjolein van Baest
Patheon Softgels B.V. De Posthoornstraat 7, 5048 AS The Netherlands
Currently, most new chemical entities under clinical development are low soluble and consequently exhibit a poor bioavailability. Lipid based formulations are known for their potential to improve bioavailability. For development of a feasible lipid formulation good solubility of the therapeutic ingredient in the lipid vehicle is required. We have developed a high throughput method for solubility screening in various lipid excipients from different categories. This methodology was tested for several model drug compounds including: Clotrimazole; Carbamazepine; and Paracetamol. For this purpose a general UHPLC method for compounds with a range of log P values supporting broad applicability for a range of small molecules was developed.
Figure 1. Chromatogram of multipurpose UHPLC method for Paracetamol, Carbamazepine, Clotrimazole, and Praziquantel.
Figure 2. Physical properties of Clotrimazole, Carbamazepine, and Paracetamol.
Table 1. Excipients selected for screening
Solubility of Clotrimazole, Carbamazepine, and Paracetamol was determined by UHPLC in >20 excipients covering medium and long chain triglycerides, lipid surfactants, and non-lipid cosolvents, see Table 1. Excess of API powder was added to each excipient in a 2 ml Eppendorf tube. Samples were stored at 37°C for 24 hours on a shaker-incubator. Samples were centrifuged at 4000 rpm for 15 minutes and an aliquot was taken for UHPLC analysis. Next, samples were subjected to an excursion to 65°C for 24 hours, followed by overnight storage at 37°C. Samples were again centrifuged at 4000 rpm for 15 minutes and equilibrium solubility was determined by UHPLC.
The UHPLC analysis was conducted by injecting 5 µl on a poroshell C18 column (2.7 µm/150X4.6 mm) at an isocratic flow of 1.0 ml/min for 5 minutes, using a mobile phase of phosphate buffer pH = 3 and acetonitrile(1/1 v/v). All details of the method are shown Table 2.
Table 2. Overview of chromatographic UHPLC conditions
Clotrimazole, Carbamazepine, and Paracetamol had sufficient difference in retention time, and did not suffer from significant interference from any of the selected excipients. A combined chromatogram containing all these model drug compounds is presented in Figure 1.
Equilibrium solubility data for the three model API’s Clotrimazole, Carbamazepine, and Paracetamol is shown in Figure 3.
Figure 3. Equillibrium solubility after >24 hours at 37 °C (blue bars) and again after >24 hours at 65 °C followed by 37 °C overnight (red bars). Values are expressed as wt.% of total. From left to right equilibrium solubility is shown in medium and long chain triglycerides, followed by glycerol mono- en diesters, propylene glycol mono- en diesters, polyoxyl (PEG) glycerides, polyglyceryl esters, and suitable cosolvents for Softgel development.
• Clotrimazole, Carbamazepine, and Paracetamol had sufficient difference in retention time, and did not suffer from significant interference from any of the selected excipients. A combined chromatogram containing all these model drug compounds is presented in Figure 1.
• Clotrimazole: Solubility was highest in Capryol 90 and Transcutol, being 15.3 ± 1.3 wt.% and 15.8 ± 0.3 wt.%, respectively.
• Carbamazepine: Solubility was highest in PolyEthyleneGlycol 400 and Transcutol, being 9.6 ± 0.01 wt.% and 9.83 ± 0.2 wt.%, respectively.
• Paracetamol: Solubility was highest in PEG400 and for lipid excipient in Labrasol, being 21.7 ± 0.6 wt.% and 11.8 ± 0.2 wt.%, respectively.
• A fast (< 5 min.) and accurate UHPLC method was successfully established meeting performance criteria for a range of model drug compounds to support high throughput solubility screening in lipid excipients, not showing any interference caused by any off the excipients selected. For Clotrimazole, and Carbamazepine solubility was evaluated as sufficient to develop a lipid based formulation. For Paracetamol solubility was highest in PEG400, indicating that a PEG-based formulation is most feasible, which may include a type IV lipid based formulation when for example combined with Labrasol. Consequently, this approach can be used to quickly assess feasibility of developing a lipid based formulation for a variety of drug compounds, including new chemical entities.
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