Title : Mannitol as eutectic forming agent for improved sublingual delivery of Cyclobenzaprine HCl
Abstract:
In solid drug product formulation, the knowledge of possible interactions between the drug substance and the excipients is a crucial point for the prediction of chemical and physical stability. Often, an excipient(s) can modify the biological activity and chemical stability of the API, even if the dissolution profile and/or chemical structure of the API are changed. In some cases, the excipient can improve the chemical and physical stability profile.
D-Mannitol is one of the excipients very often used in solid drug products and due to its physical properties, can improve or reduce the stability of the final formulation.
Following this statement, the compatibility of mannitol with Cyclobenzaprine HCl was investigated and interactions occurring were assessed.
Sublingual, transmucosal cyclobenzaprine is being developed for the treatment of fibromyalgia syndrome, post-traumatic stress disorder (PTSD), fibromyalgia-type Long COVID, acute stress disorder, agitation in Alzheimer’s disease and alcohol use disorder. Furthermore, cyclobenzaprine has potential improving the quality of sleep, as a sleep deepener, or for treating sleep disturbances.
The compatibility between API (Cyclobenzaprine HCl) and D-Mannitol was investigated by DSC and based on findings, a eutectic formation was discovered during the mechanical mixing.
In order to confirm the eutectic formation and to characterize its physical properties, several binary mixtures at di?erent ratios of API-excipient were prepared and analysed by DSC and by XRPD.
This type of interaction occurring between Cyclobenzaprine HCl and D-Mannitol (beta form) is an invariant physical interaction, because the mixture exists in thermal equilibrium when the two components are well mixed and stabilized.
The resulting solid macrostructure from a eutectic reaction depends on a few factors. The most important factor is the fact that the two solid solutions nucleate and bind together during a mechanical mixture.
This API is stable in tablet or capsule formulations for oral administration when combined with certain excipients. Increasing the absorption of a sublingual formulation (SL) can have issues with the stability of the API and the physical compositions themselves, especially when a basifying agent (a chemical compound that increases the pH of solutions after dissolution of Cyclobenzaprine HCl is present).
Because eutectics have the potential to improve dissolution, they are employed to increase permeability in solid dispersions and absorption systems. The unexpected e?ect conferred by a mannitol eutectic on cyclobenzaprine SL properties include increased stability, despite intimate contact with a basifying agent and rapid dissolution. The compaction involved in tableting provides the intimate contact between API and D- mannitoland mutual solubility sufficient for eutectic formation. The cyclobenzaprine HCl – D-mannitol eutectic compositions is an unexpected example showing that eutectics can have improved stability and enable increase absorption than their non-eutectic counterparts.
