Being a surrogate marker for bioequivalence, any change in dissolution performance on storage could be indicative of bioavailability concerns and hence needs to be critically investigated.
The first step towards a successful investigation would be to identify what factors could have contributed to the drop in dissolution.
Again, you don’t really have to sit fingers crossed hoping that that dissolution performance does not drop on storage – there are tools that can be used to predict slowdown of dissolution.
This post is a compilation of some of the common causes resulting in a drop in dissolution performance on storage and approaches to predict the slowdown in dissolution rate on storage.
Maclean et. al. published an excellent paper earlier this year on formulation dependent stability mechanisms affecting dissolution performance using three different formulations of griseofulvin tablets.
Where three different griseofulvin formulations were prepared containing microcrystalline cellulose (MCC) with either mannitol, lactose monohydrate, or dibasic calcium phosphate anhydrous (DCPA). The tensile strength, porosity, contact angle, disintegration time, and dissolution rate were measured after storage under five different accelerated temperature and humidity conditions for 1, 2, and 4 weeks. The dissolution rate was found to decrease after storage for all three batches, with the change in dissolution rate strongly correlating with the storage humidity. The changes in physical properties of each formulation were found to relate to either the premature swelling (MCC/DCPA, MCC/lactose) or dissolution (MCC/mannitol) of particles during storage. These results are also discussed with consideration of the performance- and stability-controlling mechanisms of placebo tablets of the same formulations .
Other than the material properties causing drop in dissolution, the paper also highlights another critical aspect: Identifying the equilibration period aka the optimal time to test tablets after removal from storage. Apparently, when removed from storage, tablets undergo a form of relaxation to gradually lose excess moisture absorbed under high humidity storage conditions and may cause fluctuations in results.
Fillers Effect
Molokhia et al. (1982) found that the use of mannitol and lactose resulted in increased tensile strength, slower disintegration, and slower dissolution after storage at 40◦C/90% relative humidity (RH).
This was attributed to the partial dissolution of soluble materials in the moisture contained in the tablet. Upon removal from storage, these materials may recrystallize due to the reduction in available moisture at lower humidity, resulting in the formation of new solid bridges.
Disintegrant Effect
Due to the highly hygroscopic nature of disintegrants, they are susceptible to moisture uptake during storage under high humidity which can result in premature swelling (Quodbach and Kleinebudde, 2015a).
Premature swelling of the disintegrant can result in a reduction in tensile strength (Marais et al., 2003) and changes to the pore structure of the tablet, due to gradual expansion of these particles as moisture is absorbed from the air during storage (Khan and Rhodes, 1975).
Chemical interactions or Degradation
Rohrs et al. (1999) demonstrated that a decrease in dissolution rate of Delavirdine mesylate upon exposure to high humidity was the result of a moisture-mediated interaction between croscarmellose sodium and the drug.
Aside from the material properties, a critical factor in the tablet properties after storage is the equilibration period after tablets are removed from storage.
After tablets are removed from storage, they undergo a form of relaxation during which additional moisture absorbed from the air is subsequently lost by evaporation.
This process is not instantaneous, and the length of this relaxation period is also likely to change based on the material properties or porosity, which could both influence the rate of moisture loss after removal from storage.
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