Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2013 Jun 18

PMID 23771564

Citations 25

Authors

Linda C Persson

Christopher J H Porter

William N Charman

Christel A S Bergstrom

Affiliations

Soon will be listed here.

Abstract

Purpose: To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties.

Methods: Solubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TGLC), Captex355 (medium-chain triglyceride; TGMC), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests.

Results: Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (R (2) = 0.98). A strong correlation was also found between PS80 and PEG400 (R (2) = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R (2) = 0.81, Q (2) = 0.76) and Captex355 (R (2) = 0.84, Q (2) = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure.

Conclusion: Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TGMC versus TGLC, and PS80 versus PEG400. We also show, for the first time, that solubility in TGMC and TGLC can be predicted from rapidly calculated molecular descriptors.

Citing Articles

Comparative Analysis of Chemical Descriptors by Machine Learning Reveals Atomistic Insights into Solute-Lipid Interactions.

Lange J, Anelli A, Alsenz J, Kuentz M, ODwyer P, Saal W Mol Pharm. 2024; 21(7):3343-3355.

PMID: 38780534 PMC: 11220795. DOI: 10.1021/acs.molpharmaceut.4c00080.

Solubility of Poorly Soluble Drugs in Phosphatidylcholine-Based Drug Delivery Systems: Comparison of the Loading Capacity in the Bulk Formulation and Its Dispersed State.

Grune L, Bunjes H Pharmaceuticals (Basel). 2024; 17(3).

PMID: 38543186 PMC: 10974234. DOI: 10.3390/ph17030400.

Praziquantel Fifty Years on: A Comprehensive Overview of Its Solid State.

DAbbrunzo I, Procida G, Perissutti B Pharmaceutics. 2024; 16(1).

PMID: 38258039 PMC: 10821272. DOI: 10.3390/pharmaceutics16010027.

Design, Development, Evaluation, and In Vivo Performance of Buccal Films Embedded with Paliperidone-Loaded Nanostructured Lipid Carriers.

AlMulhim F, Nair A, Aldhubiab B, Shah H, Shah J, Mewada V Pharmaceutics. 2023; 15(11).

PMID: 38004510 PMC: 10674218. DOI: 10.3390/pharmaceutics15112530.

Saquinavir-Piperine Eutectic Mixture: Preparation, Characterization, and Dissolution Profile.

Fandaruff C, Quiros-Fallas M, Vega-Baudrit J, Navarro-Hoyos M, Lamas D, Araya-Sibaja A Pharmaceutics. 2023; 15(10).

PMID: 37896206 PMC: 10609941. DOI: 10.3390/pharmaceutics15102446.

References

Rane S, Anderson B . Molecular dynamics simulations of functional group effects on solvation thermodynamics of model solutes in decane and tricaprylin. Mol Pharm. 2009; 5(6):1023-36. DOI: 10.1021/mp8000606. View

Branchu S, Rogueda P, Plumb A, Cook W . A decision-support tool for the formulation of orally active, poorly soluble compounds. Eur J Pharm Sci. 2007; 32(2):128-39. DOI: 10.1016/j.ejps.2007.06.005. View

Bergstrom C, Charman S, Nicolazzo J . Computational prediction of CNS drug exposure based on a novel in vivo dataset. Pharm Res. 2012; 29(11):3131-42. DOI: 10.1007/s11095-012-0806-5. View

Do Thi T, Van Speybroeck M, Barillaro V, Martens J, Annaert P, Augustijns P . Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS. Eur J Pharm Sci. 2009; 38(5):479-88. DOI: 10.1016/j.ejps.2009.09.012. View

Larsen D, Parshad H, Fredholt K, Larsen C . Characteristics of drug substances in oily solutions. Drug release rate, partitioning and solubility. Int J Pharm. 2002; 232(1-2):107-17. DOI: 10.1016/s0378-5173(01)00904-8. View

Kasimova A, Pavan G, Danani A, Mondon K, Cristiani A, Scapozza L . Validation of a novel molecular dynamics simulation approach for lipophilic drug incorporation into polymer micelles. J Phys Chem B. 2012; 116(14):4338-45. DOI: 10.1021/jp2104819. View

Biswas A, Sharma B, Willett J, Advaryu A, Erhan S, Cheng H . Azide derivatives of soybean oil and fatty esters. J Agric Food Chem. 2008; 56(14):5611-6. DOI: 10.1021/jf800123t. View

Huynh L, Grant J, Leroux J, Delmas P, Allen C . Predicting the solubility of the anti-cancer agent docetaxel in small molecule excipients using computational methods. Pharm Res. 2007; 25(1):147-57. DOI: 10.1007/s11095-007-9412-3. View

Pouton C . Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006; 29(3-4):278-87. DOI: 10.1016/j.ejps.2006.04.016. View

10.

Kaukonen A, Boyd B, Porter C, Charman W . Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res. 2004; 21(2):245-53. DOI: 10.1023/b:pham.0000016282.77887.1f. View

11.

Bergstrom C, Wassvik C, Johansson K, Hubatsch I . Poorly soluble marketed drugs display solvation limited solubility. J Med Chem. 2007; 50(23):5858-62. DOI: 10.1021/jm0706416. View

12.

Porter C, Pouton C, Cuine J, Charman W . Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev. 2007; 60(6):673-91. DOI: 10.1016/j.addr.2007.10.014. View

13.

Williams H, Sassene P, Kleberg K, Bakala-NGoma J, Calderone M, Jannin V . Toward the establishment of standardized in vitro tests for lipid-based formulations, part 1: method parameterization and comparison of in vitro digestion profiles across a range of representative formulations. J Pharm Sci. 2012; 101(9):3360-80. DOI: 10.1002/jps.23205. View

14.

Mansky P, Dai W, Li S, Pollock-Dove C, Daehne K, Dong L . Screening method to identify preclinical liquid and semi-solid formulations for low solubility compounds: miniaturization and automation of solvent casting and dissolution testing. J Pharm Sci. 2006; 96(6):1548-63. DOI: 10.1002/jps.20799. View

15.

Rane S, Anderson B . What determines drug solubility in lipid vehicles: is it predictable?. Adv Drug Deliv Rev. 2007; 60(6):638-56. DOI: 10.1016/j.addr.2007.10.015. View

16.

Rytting E, Lentz K, Chen X, Qian F, Vakatesh S . Aqueous and cosolvent solubility data for drug-like organic compounds. AAPS J. 2005; 7(1):E78-105. PMC: 2751500. DOI: 10.1208/aapsj070110. View

17.

Prajapati H, Dalrymple D, Serajuddin A . A comparative evaluation of mono-, di- and triglyceride of medium chain fatty acids by lipid/surfactant/water phase diagram, solubility determination and dispersion testing for application in pharmaceutical dosage form development. Pharm Res. 2011; 29(1):285-305. PMC: 3246583. DOI: 10.1007/s11095-011-0541-3. View

18.

Dai W, Dong L, Li S, Pollock-Dove C, Chen J, Mansky P . Parallel screening approach to identify solubility-enhancing formulations for improved bioavailability of a poorly water-soluble compound using milligram quantities of material. Int J Pharm. 2006; 336(1):1-11. DOI: 10.1016/j.ijpharm.2006.11.034. View

19.

Fagerberg J, Al-Tikriti Y, Ragnarsson G, Bergstrom C . Ethanol effects on apparent solubility of poorly soluble drugs in simulated intestinal fluid. Mol Pharm. 2012; 9(7):1942-52. DOI: 10.1021/mp2006467. View

20.

Lipinski C, Lombardo F, Dominy B, Feeney P . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3):3-26. DOI: 10.1016/s0169-409x(00)00129-0. View