Effects of different types of lactose and disintegrant on dissolution stability of hydrochlorothiazide capsule formulations

Abstract

Dissolution at the 20 min time point of hydrochlorothiazide (HCTZ) capsules containing Fast-Flo ® lactose, hydrous lactose, or anhydrous lactose decreased by 45, 25, and 10%, respectively, after 6 months storage at 50°C. It was hypothesized that the decrease in dissolution was due to the formation of a trace amount of formaldehyde from the hydrolysis of HCTZ in the presence of moisture liberated from the excipients and the capsule shells, and the subsequent interactions of the formaldehyde with gelatin capsule shells and corn starch present in the formulation to form insoluble compounds. In a simulated storage environment of high temperature and moisture in Conway cells and using the diffusion method, it was demonstrated that the amount of formaldehyde formed depended on the type of lactose used in the blend and followed the rank order of Fast-Flo ® > hydrous > anhydrous (pairwise p values < 0.05). In the capsule formulation containing Fast-Flo ® lactose as diluent, replacement of corn starch with a superdisintegrant such as sodium starch glycolate (Explotab ®) or croscarmellose sodium (Ac-Di-Sol ®) did not improve the dissolution stability. However, replacement of corn starch with crospovidone (Polyplasdone XL ®) as a disintegrant resulted in a capsule formulation with satisfactory dissolution stability. It was observed that in formulations which exhibited poor dissolution, the dissolution of the capsule shells was more adversely affected by formaldehyde than that of the capsule contents. Moreover, in the presence of added water, significantly less formaldehyde was detected in blends containing corn starch, Explotab ®, or Ac-Di-Sol ® compared to blends containing Polyplasdone XL ® or control (no disintegrant) probably because some of the formaldehyde generated was consumed in reactions with those disintegrants. Success of Polyplasdone XL ® in improving dissolution stability of the HCTZ capsules was attributed mainly to its moisture scavenging ability, which prevented the formation of formaldehyde and, to some extent, its non-reactivity with formaldehyde.