Preformulation Studies of a Prodrug of Δ9-Tetrahydrocannabinol

Abstract

Abstract. Preformulation studies were performed on a hemiglutarate ester prodrug of Δ 9 -tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T g close to 0°C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170°C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at −18°C but demonstrated higher degradation at 4°C, 25°C and 40°C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

Amperometric determination of promethazine in tablets using an electrochemically reduced graphene oxide modified electrode

“…Moreover, these results were View Article Online compared favorably with the values obtained for spectrophotometry 28 and HPLC. 29 In the case of sample 1, the average value obtained by amperometry showed to be the same of that found by spectrophotometry and it was very close to the result obtained by HPLC. A significance test (null hypothesis) was applied to results showed in Table 1, resulting in experimental t-values of 1.00 (for amperometry and spectrophotometry) and 0.33 (for amperometry and HPLC).…”

“…High performance liquid chromatography analyses of the commercial samples were performed following a methodology described in the literature. 29 About 15 mg of macerated tablets were weighed and dissolved in 10.0 mL of methanol. The samples were centrifuged at 5000 rpm over 15 minutes.…”

“…29 Spectrophotometry is the technique recommended by the British Pharmacopoeia for promethazine determination. 28 Table 1 presents these results together with the corresponding standard deviations calculated from three independent measurements for each sample.…”

“…Results obtained after analysis of commercial tablet samples of promethazine hydrochloride using the proposed amperometric method and the values obtained by spectrophotometry28 and HPLC 29. Labeled value: promethazine hydrochloride = 28.2 mg a Average AE standard deviation for three determinations.…”

Hot-Melt Extrusion (HME): From Process to Pharmaceutical Applications

“…Different polymers and drugs have been employed and reported in the literature for obtaining drug loaded hotmelt extruded films for various indications and are summarised in Repka and co-workers have conducted extensive research on the use of HME for the manufacture of mucoadhesive buccal films. They successfully evaluated different matrix formers and additives for the processing of the blend prior to extrusion [61,62,63,64]. In an early investigation, it was found that even though films containing exclusively HPC could not be obtained, the addition of plasticizers, such as triethyl citrate, PEG 2000/8000, or acetyltributyl citrate, allowed for the manufacture of thin, flexible, and stable HPC films [65].…”