I am developing a Fixed Dose Combination dosage form, which have an active pharmaceutical ingredient in the coat and another one in an extended release core of tablet. During development, I have encountered with problem. By increasing the amount of API in the coat, the release profile of API decreases. Whereas, there are 5, 10, and 12.5 mg of API are in the tablet coat the dissolution profile is acceptable, the dissolution profile in 25 mg
API in the coat is less than specification. I should declare that the specification of assay test and uniformity are acceptable for all doses include the largest.
Would you please guide me?
The dissolution is diffusion controlled. You need to do a study of different coatings that will give you a better profile or stick with lower amount of API.
Dear Mohammadkazem Khoeeniha ,
Such behavior is not uncommon. The release for higher doses may not reproduce the lower dose pathway since secondary reactions may act on the process by kinetic interference.
A kinetic factor may explain the observed phenomenon for 25 mg. Some API behaves differently with some excipients, depending on the relative concentration, especially in a medium with specific ionic strength, pH, pressing step on the system preparation, etc.
The behavior may be followed up by thermal analysis on the starting material or a kinetic release study to understand the involved pathways and the synergic effects generated by the concentration increase. The above comments consider the same excipients in the same amount; otherwise, this will be another concern.
An initial release burn may be observed in higher doses systems. The tablet surface may be probed using X-ray analysis in razing angle set up so that the API distribution may be inferred. Is it an intimated mixture, or is surface distributed? The raising angle X-ray experiment helps answer the question; the problem frequently happens in polymer implants where the API distribution may only be superficial after the physical implant preparation.
I guess the study is done in a simulated biological solution, so the temperature is a concern as well; it affects the release kinetics, in particular for the higher concentration.
I hope the few considerations help somehow.
Best regards,
WNM
- Badges
- Science topic
- Similar topics
- Clinical Pharmacology
- Dosing