COMPATIBILITY AND STABILITY STUDIES OF ANTIHYPERTENSIVE/EXCIPIENTS BY THERMAL METHODS, USED IN THE PREFORMULATION PHASE

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1 FARMACIA, 2014, Vol. 62, COMPATIBILITY AND STABILITY STUDIES OF ANTIHYPERTENSIVE/EXCIPIENTS BY THERMAL METHODS, USED IN THE PREFORMULATION PHASE ANCA MOISEI 1, FELICIA GLIGOR 1*, MARIUS BOJIŢĂ 2, ADRIANA CHIŞ 1, MARIA TOTAN 1, LOREDANA ANDREEA VONICA-GLIGOR 1, ADRIANA CIURBA 3 1 Lucian Blaga University, Sibiu 2 Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca 3 University of Medicine and Pharmacy of Tîrgu Mureş, Romania *corresponding author: felicia.gligor@ulbsibiu.ro 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). 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 T 0 (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 constă în investigarea calitativă a interacţiunilor dintre substanţe active antihipertensive şi posibili excipienţi pentru ghidarea procesului de preformulare a unui comprimat triplustratificat. Substanţele medicamentoase alese au fost Candesartan Cilexetil (CC), Amlodipină Besilat (AB), Hidroclorotiazidă (HCTZ) şi excipienţii Croscarmeloza sodică (AcDiSol), Stearat de magneziu (StMg), Dioxid de siliciu coloidal (Aerosil). În acest scop s-a studiat comportamentul termic (calorimetrie diferențiată (DSC) şi termogravimetrie (TG)) al CC, AB, HCTZ şi al posibililor excipienţi Aerosil, AcDiSol, StMg, precum şi a amestecurilor binare substanţă medicamentoasă excipient. Studiul a fost efectuat la T 0 (timpul iniţial) şi la diferite intervale de timp (1 lună, 2 luni, 3 luni, 6 luni şi 12 luni) în condiţii normale de temperatură şi umiditate şi în condiţii de degradare accelerată. Keywords: Antihypertensive, excipients, combination, thermal analysis

2 1240 FARMACIA, 2014, Vol. 62, 6 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. 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]. 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]. 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.

3 FARMACIA, 2014, Vol. 62, 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). 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. 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. 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.

4 1242 FARMACIA, 2014, Vol. 62, 6 The dynamic atmosphere of N 2 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 C (TG) with a 209F3 Maia Netzsch Thermogravimeter. The dynamic atmosphere of N 2 was used (purging at a rate of 20 ml/min), the heating rate was 10 C/min. 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 (ΔH= mJ) with a melting point T onset =201.4 C. The thermal behaviour of the physical mixture AB and AcDiSol (sodium croscarmellose) is shown in Figure 1 at the initial time T o and at the five analysed times in normal and accelerated degradation conditions. Figure 1. DSC Thermograms, curves of Amlodipine + AcDiSol

5 FARMACIA, 2014, Vol. 62, The TG curve showed a weight loss of 64.17% between and 700 C due to the decomposition of amlodipine. The thermograms are shown in Figure 2, and the obtained values are summarized in Table I. The results obtained from the DSC and TG analyses of the binary mixture AB AcDiSol are shown in Table I. Time Figure 2. TG Thermograms, curves of Amlodipine + AcDiSol Table I. DSC and TG results of the binary mixture AB AcDiSol DSC TG Conditions Tonset ( C) Tpek (mw/mg) Enthalpy (mj/mg) Tonset ( C) T month months months NC months months month months months AC months months NC = Normal Conditions; AC = Accelerated Conditions Tinflection ( C) Weight loss (%)

6 1244 FARMACIA, 2014, Vol. 62, 6 The DSC curve of CC at time To shows an endothermic peak (ΔH= mj) between C. The DSC curve of the physical mixture of CC and Aerosil (Colloidal silica), (Figure 3), showed that there is no incompatibility between the two substances and that they are stable over time, having a melting point around 168ºC, values shown in Table II. Figure 3. DSC Thermograms, curves of Candesartan + Aerosil The TG thermograms of the same binary mixture are presented in Figure 4, and the obtained values are listed in Table II. We may notice a weight loss of 47.4% and a melting lapse T onset = C and T endset = 306 C with an inflection point at C.

7 FARMACIA, 2014, Vol. 62, Figure 4. TG Thermograms, curves of Candesartan + Aerosil Table II. DSC and TG results of the binary mixture Candesartan + Aerosil DSC TG Time Conditions Tonset ( C) Tonset ( C) Tonset ( C) Tinflection ( C) Weight loss (%) T month months months NC months months month months months AC months months NC = Normal Conditions; AC = Accelerated Conditions

8 1246 FARMACIA, 2014, Vol. 62, 6 The DSC curve of HCTZ shows at time To an endothermic peak (ΔH = mj) between C which can be observed in Figure 5, and the results are listed in Table III. In the binary mixture, we notice a peak shift at T o towards a lower, insignificant, temperature, and under accelerated conditions we observe a broadening of the peak, due to a possible degradation. It is recommended to use magnesium stearate in a lower concentration. Figure 5. DSC Thermograms, curves of HCTZ + Mg. Stearate The TG thermograms of the same binary mixture of HCTZ and magnesium stearate are shown in Figure 6 and the obtained values are listed in Table III. We notice a weight loss of 48.82% and a melting lapse T onset = 301 C and T endset = C with an inflection point at C.

9 FARMACIA, 2014, Vol. 62, Time Figure 6. TG Thermograms, curves of HCTZ + Mg. Stearate Table III. DSC and TG results of the binary mixture HCTZ + Mg. Stearate DSC TG Conditions Tonset ( C) T ndset ( C) Tpek (mw/mg) T month months months NC months months month months months AC months months NC = Normal Conditions; AC = Accelerated Conditions Enthalpy (mj/mg) Tonset ( C) Tinflection( C) Weight loss (%)

10 1248 FARMACIA, 2014, Vol. 62, 6 Conclusions The analysis of the thermograms shows that there are no significant changes, each of the analysed active substances are found unchanged in the mixtures, indicating that there are no major interactions between them and the excipients. We conclude that all the analysed excipients are compatible and can be used to obtain modified release formulations containing candesartan, amlodipine and hydrochlorothiazide. References 1. Gradman A.H., Basile J.N., Carter B.L., Bakris G.L., Am. Soc. of Hypertension Writing Group, Combination therapy in hypertension. J. of the Am. Soc. of Hypertension, 2010; 4(2): Gradman A.H., Strategies for combination therapy in hypertension. Curr. Opin. Nephrol. Hypertens., 2012; 21(5): Dinte E., Bodoki E., Leucuta S., Iuga C.A., Compatibility studies between drugs and excipients in the preformulation phase of bucal mucoadhesive systems. Farmacia, 2013; 61(4): MacGregor G.A., Antonios T.F., He F.J., D29 The efficacy of candesartan; an angiotensin II type I receptor antagonist alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in patients with moderate-to-severe essential hypertension. Am. J. of Hypertens., 1997; 10(4-2): 112A. 5. Rus L.M., Tomuta I., Iuga C., Maier C., Kacso I., Borodi G., Bratu I., Bojita M., Compatibility Studies of indapamide / pharmaceutical excipients used in tablet preformulation. Farmacia, 2012; 60(1): Rowe R.C., Sheskey P.J., Quinn M.E., Handbook of Pharmaceutical Excipients, 6 th edition. 7. Bharate S.S., Bharate S.B., Bajaj A.N., Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J. Excipients and Food Chem., 2010; 1(3): Manuscript received: January 2014