This work aimed at developing enalapril maleate granules in order to improve its stability in solid dosage form. Granules were prepared by hot melt granulation using a fluidized bed apparatus. Gelucire 50/13®, polyethylene glycol 6000 e Poloxamer 407® were studied and compared as binders in 2 × 2 factorial designs where the proportions of enalapril maleate, binders and spray dried lactose were varied. The granulation process resulted in high yields and granule sizes that indicated the prevalence of particles coating. Furthermore, the granules obtained showed adequate flowability and a fast dissolution rate of enalapril maleate with almost 100% of the drug released in 10 min. The stability of enalapril maleate in hard gelatin capsules showed that the drug stability was greatly increased in granules, since for raw drug, the remaining content of enalapril maleate after 91 days was 68.4% and, for granules, the content was always above 93%. This result was confirmed by the quantification of the degradation products, enalaprilat and diketopiperazine, which were found in very low content in granules samples. The results demonstrate that fluidized bed hot melt granulation with hydrophilic binders is a suitable alternative for improving the chemical stability of enalapril maleate.

Enalapril maleate (EM) is a widely used anti-hypertensive drug which is unstable when mixed with excipients. Enalaprilate and diketopiperazine (DPK) are the main degradation products of enalapril. The in situ preparation of enalapril sodium salt (NaE) has been used to improve drug stability in dosage forms; however, gas release and product rejection ensue when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. This study evaluated the effect of stearic acid (SA) on enalapril stability in microcrystalline cellulose (MCC) pellets containing EM or NaE. MCC pellets containing SA were prepared by the extrusion-spheronization technique and characterized. Enalapril stability and dissolution were then evaluated. DPK and enalaprilate formation were reduced by the addition of SA in pellets containing EM. The overall enalapril degradation in these formulations was lower when compared with pellets containing EM or even NaE prepared without SA. The immediate-release characteristic was maintained by the addition of 5% crospovidone to all the formulations tested. The incorporation of SA into NaE pellets resulted in unexpected enalapril degradation, caused by the interaction of these compounds, as suggested by a thermal analysis of the SA-NaE binary mixture. The findings presented here showed that formulations containing SA could substitute the formation of NaE, since they provide better enalapril stability in solid dosage forms. In addition, it is suggested that the stabilization effects would be observed for other N-carboxyalkyl dipeptide analogs with angiotensin converting enzyme inhibition activity, since these new entities share the same degradation pathway of enalapril.

Enalapril maleate is a widely used drug, which is chemically unstable when mixed with excipients resulting in enalaprilat and diketopiperazine as the main degradation products. The preparation of enalapril sodium salt has been used to improve drug stability in solid dosage forms; however, product rejection is observed when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. In this study, granules were prepared by melting granulation using stearic acid or glyceryl monostearate, with a view to developing more stable enalapril maleate solid dosage forms. The granules were prepared in a laboratory-scale high shear mixer and compressed in a rotary machine. Size distribution, flow properties, in vitro drug release and enalapril maleate chemical stability were evaluated and compared with data obtained from tablets prepared without hydrophobic binders. All formulations showed good physical properties and immediate drug release. The greatest improvement in the enalapril maleate stability was observed in formulations containing stearic acid. This study showed that hot melting granulation could be successfully used to prepare enalapril maleate granules which could substitute the in situ formation of enalapril sodium salt, since they provided better enalapril stability in solid dosage forms.