(T1530-03-14) Importance of β Cyclodextrin Substitution Level and Type for Solubilization and Stabilization of Poorly Soluble APIs in Parenteral Dosage Forms

Purpose: Parenteral formulations often contain higher concentrations of excipients than active ingredients. These excipients enhance safety, provide solubility, better stability, increase bioavailability, improve patient compliance, or generally improve drug performance^1,2. Each year an increasing number of novel APIs demonstrate poor aqueous solubility, in certain therapeutic areas 90% of new drugs are poorly water soluble³. As therapies shift toward more challenging molecules, more sophisticated methods of solubilizing and stabilizing than can be afforded by traditional excipients must be explored in the formulation and processing⁴. Cyclodextrins such as Cavitron™ hydroxypropyl β cyclodextrin (HP-β-CD) are cyclic oligosaccharides of varying ring diameter capable of solubilizing pharmaceutical actives while having a favorable toxicological profile. Cyclodextrins aid in solubilization via complexation of the active molecule within the hydrophobic cavity formed between the ring of glucose units, the size of the cavity helps guide the interaction between the host and guest molecule⁵. The work detailed here explores the complexation efficiency of hydroxypropyl substituted β cyclodextrins (HP-βCD’s) of varying substitution levels and sulfobutyl ether substituted β cyclodextrin with both large and small molecules (fig 1).

Methods: A rational step-by-step formulation approach was used to determine the solubility isotherms for, 2 small molecule API’s (carbamazepine, voriconazole) and one large molecule API (carfilzomib) respectively. Each isotherm was determined in water at various relevant pHs (if the API was ionizable) using both Cavitron™ W7 HP5 (HP-β-CD HP5) and W7 HP7 Pharma (HP-β-CD HP7) as marketed by Ashland Inc. with hydroxypropyl groups replacing the ring facing hydroxyl groups on 5 and 7 of the glucose units respectively, as well as sulfobutylether β-cyclodextrin (SBE-β-CD) to test the impact of degree of substitution and substituent type on complexation efficiency. API solubility was analyzed via HPLC, and the maximum concentration of cyclodextrin required to achieve one dose was measured. Voriconazole and carfilzomib samples were lyophilized via a standard cycle on a VirTis benchtop lyophilizer. Stability of the formulated solutions was performed at 25°C / 60% RH and 40°C / 75% RH.

Results: Small Molecules For carbamazepine both Cavitron™ W7 HP5 and Cavitron™ W7 HP7 significantly increase solubility. The degree of HP-β-CD substitution did not impact complexation of carbamazepine. Both, Cavitron™ W7 HP5 and Cavitron™ W7 HP7 demonstrated better solubility (26 mg/ mL and 25 mg/ mL respectively) than SBE-β-CD (23 mg/ mL) and the mechanism of complexation seems to be the same for both Cavitron™ W7 HP5 and HP7. Addition of other common excipients such as PEG400, propylene glycol and citric acid had very little impact on the solubility of carbamazepine. Formulating a generic version of Carnexiv™ (10 mg / mL carbamazepine with 250 mg/ml SBEβCD) with Cavitron™ W7 HP5 or Cavitron™ W7 HP7 allowed reduction of the required cyclodextrin solubilizer by 100 mg/ml which amounts to a 2 g reduction of cyclodextrin solubilizer per dose, which would significantly reduce the amount of cyclodextrin administered to the patient while still performing as expected. The solubility of voriconazole was significantly increased with both Cavitron™ W7 and Cavitron™ W7 HP7. Changing the degree of substitution of HPβCD and substituent type had only a modest effect, with the lower degree of substitution Cavitron™ W7 HP5 (41 mg/mL) performing much better and the higher degree of substitution Cavitron™ W7 HP7 (35 mg/mL) performing slightly better than SBEβCD (33 mg/mL) in 40 w/w % solutions of solubilizer. Cavitron™ W7 HP5 could be considered an alternative solubilzer to SBEβCD for formulating voriconazole solutions thus requiring less cyclodextrin for obtaining a clear solution, which can be lyophilized and easily reconstituted. Large molecules: Cavitron™ W7 HP5 and Cavitron™ W7 HP7 significantly increase solubility of carfilzomib especially at higher concentrations, lower concentrations of SBEβCD showed higher solubility of carfilzomib then tapered off. Degree of substitution of HPβCD plays a role in solubilizing carfilzomib, the lower degree of substitution performing better. Cavitron™ W7 HP5 demonstrated better solubilization than SBEβCD, while Cavitron™ W7 HP7 demonstrated similar solubility compared to SBEβCD. Cavitron™ W7 HP5 could be considered an alternative solubilizer for carfilzomib formulations. Thus requiring less cyclodextrin for obtaining a clear solution, which can be lyophilized and easily reconstituted at a higher concentration that is currently formulated, allowing for lower volume injections.

Conclusion: Cavitron™ hydroxypropyl b cyclodextrins are valuable ingredients for pharmaceutical formulations of otherwise insoluble API’s by providing a wide range of benefits including improved solubilization and stabilization of both small and large molecules. Cyclodextrins can provide solutions to formulating insoluble drug products containing active ingredients with very low solubility, opening the door to otherwise inaccessible treatments.

References: 1] Pramanick, Sougata & Chandel, Vikas & Singodia, Deepak. “Excipient Selection In Parenteral Formulation Development” Pharma Times. 45. (2013). 65 - 77.
2] Bindhu Madhavi Rayaprolu, Jonathan J. Strawser & Gopal Anyarambhatla “Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics” Drug Development and Industrial Pharmacy, 44:10, (2018) 1565-1571.
3] Youssef W. Naguib, Hannah L. O’Mary, Zhengrong Cui, Alan B. Watts “Injectable Formulations of Poorly Water-Soluble Drugs” in Formulating Poorly Water Soluble Drugs (AAPS, volume 22, 2016), Pages 257-293.
4] Jorgensen L, Hostrup S, Moeller EH, Grohganz H. “Recent trends in stabilising peptides and proteins in pharmaceutical formulation - considerations in the choice of excipients”. Expert Opin Drug Deliv. Nov;6 (2009) 1219-30.
5] Thorsteinn Loftsson, Marcus E. Brewster, “Cyclodextrins as Functional Excipients: Methods to Enhance Complexation Efficiency” Journal of Pharmaceutical Sciences, 101: 9, (2012) 3019-032.


Carbamazepine Isotherm


Voriconazole Isotherm


Carnexiv Formula Card