COMPATIBILITY AND STABILITY STUDIES OF …

1 FARMACIA, 2014, Vol. 62, 6 1239 COMPATIBILITY AND STABILITY STUDIES OF antihypertensive / excipients BY thermal methods , USED IN THE PREFORMULATION PHASE ANCA MOISEI1, FELICIA GLIGOR1*, MARIUS BOJI 2, ADRIANA CHI 1, MARIA TOTAN1, LOREDANA ANDREEA VONICA-GLIGOR1, ADRIANA CIURBA3 1 Lucian Blaga University, Sibiu 2 Iuliu Ha ieganu University of Medicine and Pharmacy, Cluj-Napoca 3 University of Medicine and Pharmacy of T rgu Mure , Romania *corresponding author: Abstract The objective of this study was to investigate the quality of the interactions between the active antihypertensive substances and the possible excipients in order to guide the preformulation process of a triple layered tablet. The active substances chosen were Candesartan Cilexetil (CC), Amlodipine Besylate (AB), Hydrochlorothiazide (HCTZ) and the excipients were Croscarmellose sodium (AcDiSol), Magnesium Stearate (StMg), and Colloidal silica (Aerosil).

2 For this purpose we studied the thermal behaviour (differential scanning calorimetry - DSC and thermogravimetry -TG) of CC, AB, HCTZ and the possible excipients Aerosil, AcDiSol, StMg and of the binary mixtures active pharmaceutical ingredient (API) - excipient. The study was performed at T0 (initial moment) and at different time intervals (1 month, 2 months, 3 months, 6 months and 12 months) under normal temperature and humidity conditions and under accelerated degradation conditions. Rezumat Obiectivul acestui studiu const n investigarea calitativ a interac iunilor dintre substan e active antihipertensive i posibili excipien i pentru ghidarea procesului de preformulare a unui comprimat triplustratificat. Substan ele medicamentoase alese au fost Candesartan Cilexetil (CC), Amlodipin Besilat (AB), Hidroclorotiazid (HCTZ) i excipien ii Croscarmeloza sodic (AcDiSol), Stearat de magneziu (StMg), Dioxid de siliciu coloidal (Aerosil).

3 N acest scop s-a studiat comportamentul termic (calorimetrie diferen iat (DSC) i termogravimetrie (TG)) al CC, AB, HCTZ i al posibililor excipien i Aerosil, AcDiSol, StMg, precum i a amestecurilor binare substan medicamentoas excipient. Studiul a fost efectuat la T0 (timpul ini ial) i la diferite intervale de timp (1 lun , 2 luni, 3 luni, 6 luni i 12 luni) n condi ii normale de temperatur i umiditate i n condi ii de degradare accelerat . Keywords: antihypertensive , excipients , combination, thermal analysis FARMACIA, 2014, Vol. 62, 6 1240 Introduction The combined therapy with calcium channel blockers, angiotensin II blockers and diuretics is recommended as one of the most effective and commonly used in treating hypertension [4]. The development of certain oral modified release formulations containing one or more active antihypertensive substances is a highly actual field of research, because it is an effective therapeutic alternative compared to the conventional forms.

4 The objective of the modified release multiple forms in oral administration is to control the release of the therapeutic agents and the absorption in the gastrointestinal tract. Such a dosage form reduces the frequency of the administration, the adverse effects, and improves the cost - effectiveness ratio of the treatment and also the patient s compliance [1, 2]. The formulation of a medicine involves mixing the active substance with different excipients in order to facilitate the administration, to allow the release of the active component and to provide STABILITY against environmental degradation [7]. The STABILITY and the bioavailability of a medicine depends heavily on the chosen excipients , on their concentration and on their interaction with the active substance; therefore the excipients cannot be considered inert or inactive substances [6].

5 One of the essential conditions for obtaining the optimal formulation is the absence of interactions between the active substance and the excipients or between the excipients . The selection of the suitable excipients during the preformulation STUDIES is a very important stage in which the physicochemical properties of the active substances are studied alone and in combination with excipients , thus obtaining detailed information on their COMPATIBILITY and STABILITY [5, 7]. The most frequently used methods for investigating the physicochemical properties and detecting the interactions between the medicinal substances and the excipients are the thermal analyses (differential scanning calorimetry (DSC), DTA, DTG), the spectroscopic, chromatographic methods [3].

6 The thermal analysis, the most widely used, is a thermo-analytical technique allowing the study of the endothermic or exothermic changes of a sample, while it is subjected to a controlled temperature program, in order to obtain more information on its structure and behaviour. For drug analysis, the thermal analysis methods are used to confirm certain structures, to estimate the STABILITY of certain substances, mixtures or formulations. FARMACIA, 2014, Vol. 62, 6 1241 The objective of this study was to investigate the quality of the interactions between the active antihypertensive substances and the possible excipients in order to guide the preformulation process of a triple layered tablet. The active substances chosen were Candesartan Cilexetil (CC), Amlodipine Besylate (AB), Hydrochlorothiazide (HCTZ) and the excipients were Croscarmellose sodium (AcDiSol), Magnesium Stearate (StMg), and Colloidal silica (Aerosil).

7 For this purpose we studied the thermal behaviour (differential scanning calorimetry - DSC and thermogravimetry -TG) of CC, AB, HCTZ and the possible excipients Aerosil, AcDiSol, StMg and of the binary mixtures active pharmaceutical ingredient (API) - excipient. Materials and methods Materials Candesartan Cilexetil (Aurobindo Pharma LTD) (CC), Amlodipine Besylat (Hetero Drugs Limited) (AB), Hydrochlorothiazide (Changzhou Pharmaceutical) (HCTZ), Croscarmellose sodium SD-711 (AcDiSol, FMC Biopolymer Ireland) (AcDiSol), Magnesium Stearate (Mosselman, Belgium) (StMg), Colloidal silica (Aerosil). The physical mixtures of CC, AB, HCTZ with the selected excipients have been prepared in a ratio of 1:1 (m/m), by simply mixing the components in an agate mortar and pestle for about 10 minutes and were examined both alone and in binary mixtures.

8 This ratio was chosen in order to maximize the probability of tracking any kind of interaction. Equipment and method The analyses have been conducted in the laboratories of Research, Development and Quality Control within Polipharma Industries Sibiu, Romania. Initially, the analysis of the individual active substance and of the excipients was conducted individually, and then we switched to binary mixtures. We continued to study the behaviour of the mixtures; the samples were stored in the STABILITY chambers (MMM Medcenter), both in normal conditions (NC - B100992) - temperature 25 C and 60% humidity and in accelerated degradation conditions (AC- B100991) at a temperature of 40 C and 75% humidity, and were analysed at T1-1 month, T2-2 months, T3-3 months, T4-6 months, T5-12 months.

9 Differential scanning calorimetry (DSC) The analysis of the behaviour of the active substances and of the excipients , as well as that of the binary mixtures was achieved by exposure to a temperature of 25 to 400 C (DSC), with a 200F3 Maia Netzsch Differential Scanning Calorimeter. FARMACIA, 2014, Vol. 62, 6 1242 The dynamic atmosphere of N2 was used (purging at a rate of 50 mL/min), and the heating rate was 10 C/min using aluminium crucibles. Thermogravimetric analysis (TG) The analysis of the behaviour of the active substances and the excipients , as well as of the binary mixtures, was achieved by exposure to a temperature of 30-700 C (TG) with a 209F3 Maia Netzsch Thermogravimeter. The dynamic atmosphere of N2 was used (purging at a rate of 20 mL/min), the heating rate was 10 C/min.

10 Using aluminium crucibles. The weighing (measurement) of the samples was performed using the analytical scale Excellence Plus 5 decimals XP205T M Metler Toledo. Results and Discussion After a preliminary analysis, out of the 13 analysed excipients , five were selected, for further COMPATIBILITY and STABILITY STUDIES . The selected binary mixtures AB + AcDiSol, HCTZ + Mg. St, CC + Aerosil, were obtained in a ratio of 1: 1 (m/m). The DSC thermo-analytical curve of AB showed a first endothermic event between and 208 C ( H= ) with a melting point Tonset= C. The thermal behaviour of the physical mixture AB and AcDiSol (sodium croscarmellose) is shown in Figure 1 at the initial time To and at the five analysed times in normal and accelerated degradation conditions. Figure 1.