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Tablet Formulation Studies on Recrystallized Active Pharmaceutical Ingredients of Valsartan and Olmesartan Medoxomil

Department of Pharmaceutics and Biotechnology, KVSR Siddhartha college of pharmaceutical sciences, Vijayawada, AP, India

Article Info:

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Article History:

Received 11 October 2021

Reviewed 13 November 2021

Accepted 21 November 2021

Published 15 December 2021

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Cite this article as:

Rao TP, Nalluri BN, Tablet Formulation Studies on Recrystallized Active Pharmaceutical Ingredients of Valsartan and Olmesartan Medoxomil, Journal of Drug Delivery and Therapeutics. 2021; 11(6-S):1-8

DOI: http://dx.doi.org/10.22270/jddt.v11i6-S.5091

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*Address for Correspondence:

TP. Rao, Buchi N. Nalluri, Department of Pharmaceutics and Biotechnology, KVSR Siddhartha college of pharmaceutical sciences, Vijayawada, AP, India

Abstract

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Both the Valsartan (VAL) and Olmesartan medoxomil (OLM) are widely prescribed anti-hypertensive agents with angiotensin II type I receptor antagonistic activity. Both VAL and OLM are type of BCS class II drugs and having a low and variable oral bioavailability. Recrystallization of VAL and OLM from different organic solvents improved its aqueous solubility and thereby in vitro dissolution properties. In the present investigation, tablets containing Valsartan (VAL), Olmesartan medoxomil (OLM and) recrystallized products were prepared by direct compression method and evaluated for drug content, uniformity of weight, hardness, friability, disintegration time and dissolution properties. All the tablets fulfilled the compendial requirements with regarding to weight variation, friability and disintegration time etc for immediate release tablets. The DP₁₅ (drug percent dissolved at 15 min) values for V-1 (tablets of VAL), V-4 (tablets of methanol recrystallized product with crospovidone as disintegrant) and DIOVAN™ 40mg tablet formulations are 45.97, 98.95 and 82.65 respectively and V-4 formulation showed higher dissolution rate when compared to other formulations. The DP₁₅values of O-1(tablets of OLM), O-4 (tablets of acetonitrile recrystallized product with crospovidone as disintegrant and OLMY™ (20mg) tablet formulations are 29.25, 99.93 and 84.82 respectively. O-4 tablet formulations showed higher dissolution rate when compared to other tablet formulations.

Keywords: Valsartan, Olmesartan medoxomil, Recrystallization, Aqueous solubility

Both the Valsartan (VAL) and Olmesartan medoxomil (OLM) are widely prescribed anti-hypertensive agents with angiotensin II type I receptor antagonistic activity. Both VAL and OLM belongs to BCS class II type drugs and are having a low and variable oral bioavailability (VAL-10-35% and OLM -29%) and their absorption is dissolution rate limited^1-4. Oral bioavailability of drugs from solid dosage forms (tablets, capsules) depends mainly on solubility of drug particles in GI fluids and permeability of dissolved drug molecules across GI membranes⁵.

Several techniques were reported to increase dissolution properties of VAL and thus enhancing its oral BA including solid dispersions, cyclodextrin inclusion complexes, formulation of self-microemulsifying drug delivery system (SMEDDS), reduction in particle size (micro- and nanosuspensions), etc^6-9. Similarly, several approaches were reported to increase dissolution properties of OLM in order to enhance its oral BA including formulation of self-microemulsifying drug delivery system (SMEDDS), reduction in particle size (nanosuspensions), etc^10-12.

Crystal morphology has a great effect on the physicochemical properties of the drug and many drug molecules exist in more than one crystal forms (polymorphism). Modifying and controlling the crystalline nature of a drug via recrystallization can improve several pharmaceutical properties of drugs like stability, solubility, rate of dissolution, etc. which in turn may affect the absorption and BA of the drug¹³. Previously authors reported the effect of recrystallization on solubility and in vitro dissolution properties of VAL and inferred in significant improvement with recrystallized products (especially methanol solvent recrystallized product) when compared to untreated VAL¹⁴. Similarly, in an earlier study on the evaluation of the effect of recrystallization on various properties of OLM inferred in significant improvement in aqueous solubility and in vitro dissolution properties of recrystallized products (especially acetonitrile solvent recrystallized product) when compared to untreated OLM¹⁵.

The aim of the pharmaceutical technologist is to formulate available medicament into a suitable dosage form depending upon factors such as physicochemical properties of the drug compound, route of administration, age and diseased condition. Amongst the various routes of administration, the oral route is most commonly used and preferred. The dosage forms available for oral administration are liquids like solutions, suspensions and emulsions and the solids like powders, tablets and capsules etc. The physical state of most of the drugs being solid, they are administered in solid dosage forms. Major proportions of the available dosage forms comprise of solids divided into unit and bulk dosage forms. Tablets and capsules generally exemplify unit dosage forms. Hence, in the present investigation, tablets containing VAL, OLM and recrystallized products were prepared by direct compression method and evaluated for drug content, uniformity of weight, hardness, friability, disintegration time and dissolution properties.

VAL and OLM (Gift samples from M/s Aurobindo Pharma, Hyderabad, India), Crospovidone (CP) (BASF, USA), Croscarmellose sodium (CCS) (FMC Biopolymer, USA), Sodium starch glycolate (SSG) (JRS Pharma, USA), Microcrystalline cellulose (MCC, PH101) (FMC Biopolymer, USA), Talc (Loba chemie, India), Magnesium stearate (Loba chemie, India) were used. All the solvents were of reagent grade.

Two grams of both VAL and OLM were added to 5mL of a specific pure organic solvent (methanol for VAL and acetonitrile for OLM) in seperate 15 mL beakers and heated slowly to 45°C to afford a supersaturated solution. The resulting mixture was then cooled down to room temperature. The resulting recrystallized drug was then collected, dried at 40°C for 15min, and passed through a #80 sieve to obtain a product of uniform particle size. The powdered drug was packed in glass bottles and stored in a desiccator until use^14,15.

As per the formulae mentioned in the Table- 1 and 2 required quantities of VAL, OLM, VMET and OACN respectively were mixed with filler i.e, microcrystalline cellulose in a mortar for 10 minutes. Then sodium starch glycolate/croscarmellose sodium/crospovidone, talc and magnesium stearate were added and mixed thoroughly for additional three minutes. The resulting blend was then compressed to tablets on a single punch tablet press (Cadmach India Ltd) to a hardness of 4 kg/cm².

Ingredients(mg/tablet)	V-1	V-2	V-3	V-4
VAL	40	-	-	-
VMET	-	40	-	-
VMET	-	-	40	-
VMET	-	-	-	40
SSG	10	10	-	-
CCS	-	-	10	-
CP	-	-	-	10
MCC	147	147	147	147
Magnesium stearate	1.5	1.5	1.5	1.5
Talc	1.5	1.5	1.5	1.5
Total weight of tablet (mg)	200	200	200	200

Ingredients(mg/tablet)	O-1	O-2	O-3	O-4
OLM	20	-	-	-
OACN	-	20	-	-
OACN	-	-	20	-
OACN	-	-	-	20
SSG	10	10	-	-
CCS	-	-	10	-
CP	-	-	-	10
MCC	167	167	167	167
Magnesium stearate	1.5	1.5	1.5	1.5
Talc	1.5	1.5	1.5	1.5
Total weight of tablet (mg)	200	200	200	200

Formulation powder blends of VAL, OLM and recrystallized products were evaluated for pre compression parameters like angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. The results were given in Table- 3 for VAL and Table- 4 for OLM.

Powder blends of VAL, OLM and recrystallized products were subjected to DSC and FTIR studies for the identifying any incompatibility with excipients used in the tablet formulations. The DS thermograms and FTIR spectra were shown in Figs- 1 -4.

The tablets were evaluated for properties like drug content, uniformity of weight, hardness, friability, disintegration time and dissolution properties.

Five tablets were weighed and powdered in a mortar. An accurately weighed powder sample equivalent to 40 mg of VAL and 20 mg of OLM was transferred to a 100mL volumetric flask and the VAL and OLM was extracted in to 75mL of methanol. This solution was filtered and collected in to a 100mL volumetric flask and made volume up to 100mL with methanol. The solution was further diluted and the absorbance was measured at 250 nm for VAL and 258 nm for OLM respectively. The estimations were carried out in triplicate. The results were reported in Table- 5.

The individual and total weight of twenty tablets from each batch was determined. Percentage deviation of the individual weights from the average weights was calculated. The results were given in Table-5.

The hardness of the tablets was measured with a Monsanto hardness tester (M/s Campbell Electronics, India). The results were given in Table- 5. The results reported were average of 10 tablets for each formulation.

The percentage loss in weight of a sample of 10 tablets in each formulation was determined in Roche friabilator (M/s Remi India) for 4 minutes (100 revolutions). The results were given in Table- 5.

The disintegration time was determined for 6 tablets with a USP/IP disintegration apparatus (M/s Campbell Electronics, India). The results were given in Table- 5.

In vitro dissolution studies of formulations were carried out in 1000 mL of phosphate buffer of pH 6.8 for VAL as per USP and 900 mL for OLM using USP XXI Type II Dissolution Rate Test Apparatus (Model DS 8000, M/S Lab India). A speed of 50 rpm and a temperature of 37°±1°C were used in each test. Five mL aliquots were withdrawn at predetermined time intervals, filtered using a 0.45 m nylon disc filter and replaced with 5 mL of fresh dissolution medium. The filtered samples were suitably diluted if necessary and analyzed for VAL and OLM concentrations by measuring absorbance at 250 nm and 258 nm respectively. The dissolution experiments were conducted in triplicate. Percent VAL and OLM dissolved at different time intervals and various dissolution parameters were given in Tables- 5.6 & 5.7 and dissolution profiles were shown in Figs- 5.17 & 5.18.

Optimized formulation was subjected to stability studies by placing in a stability chamber (Remi, India) for three months. Temperature and relative humidity was maintained at 40 ± 2^o C and 75 ± 5 % relative humidity. The tablets were evaluated for drug content, hardness, friability, disintegration time and percent dissolved at 15 minutes.

Formulation powder blends of VAL, OLM and recrystallized products were evaluated for pre compression parameters like angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. The flow and compressibility properties of powder blends with recrystallized products of VAL and OLM were improved, when compared to VAL and OLM.

The DSC thermograms of VAL and OLM and recrystallized products were shown in Figs- 1 2. The melting endotherm of VAL was observed at 103ᴼ C, corresponds to its melting point and similarly with recrystallized product formulation blends, a broad endothermic appeal was observed in range of 50-150ᴼ C as observed with the recrystallized products of VAL. These results indicate that there is no drug-excipient interaction with the blends of VAL and its recrystallized product of VMET. The melting endotherm of OLM was observed at 187ᴼ C, corresponds to its melting point and similarly with recrystallized product formulation blends a similar endothermic peak was observed and is an indication of no drug-excipient interaction with the blends of OLM and its recrystallized product of OACN.

The FTIR spectras were also confirmed the results of DSC studies indicating no excipient interaction with VAL, OLM and recrystallized products. VAL has two characteristic carbonyl absorption bands at 1725 and 1598 cm^-1 that correspond to carboxyl and amide carbonyl stretching respectively. The peak at 3393cm^-1 indicates the presence of an N-H functional group. The band at 2961cm^-1indicates the presence of C-H group stretching vibration. The spectrum reveals the characteristic peaks in the typical range at 1205-1052 cm^-1confirms the presence of characterisitc tetrazole ring in the VAL. The characteristic peaks of OLM at 3290.86 cm^-1 (N-H stretching), 1831.90 cm^-1(C-O stretching in dioxone ring), and 1707.29 cm^-1 (C-O stretching) were observed. All the significant bands of VAL and OLM were retained in the formulation blends indicating no excipient interaction with VAL, OLM and recrystallized products. The spectras were shown in Figs- 3 & 4.

Tablet formulations containing VAL, VMET (dose of 40 mg) and OLM, OACN (dose of 20 mg) were prepared by direct compression method as per the formulae given in Tables-1 & 2. The tablets were evaluated for drug content, uniformity of weight, hardness, friability and disintegration time and dissolution rate studies. The results are summarized in Tables- 5.5 -5.10 and shown in Figs- 5.17 and 5.18.

Formulation	Drug content (mg/tab)	Mean weight (mg) (Percent deviation)		Hardness (Kg/cm²)	Friability (% wt loss)	Disintegration time (min)
V-1	40.20 ± 1.3	200.85 (-0.09 to +1.27)	5 ± 0.00		0.34 ± 0.05	5 ± 0.25
V-2	39.98 ± 0.97	201.45 (-0.25 to +2.10)	4.5 ± 0.00		0.47 ± 0.07	4.25 ± 0.20
V-3	39.82 ± 0.85	201.85 (-0.07 to +2.39)	5 ± 0.00		0.59 ± 0.04	3.5 ± 0.15
V-4	39.51 ± 1.1	200.65 (-0.19 to +3.31)	4.5 ± 0.00		0.44 ± 0.06	3.10 ± 0.25

Formulation	Drug content (mg/tab)	Mean weight(mg) (Percent deviation)		Hardness (Kg/cm²)	Friability (% wt loss)	Disintegration time (min)
O-1	20.09 ± 0.55	202.20 (-0.41 to +2.56)	4.5 ± 0.00		0.42 ± 0.04	4.25 ± 0.10
O-2	19.95 ± 0.69	202 (-0.15 to +2.96)	4.5 ± 0.00		0.49 ± 0.06	4 ± 0.12
O-3	20.28 ± 0.47	203.70 (-0.14 to +3.15)	4.5 ± 0.00		0.59 ± 0.05	4.10 ± 0.15
O-4	20.13 ± 0.63	202.35 (-0.81 to +3.27)	5 ± 0.00		0.63 ± 0.04	3.52 ± 0.12

The drug content of tablets was within the range of 100 ± 5% of labeled claim and the results were satisfactory (Tables 3 &4).

The results were summarized in Tables 3 &4 showed that a good degree of uniformity of weight was achieved for all the batches of tablet formulations prepared. The percent deviation did not exceed 7.5%, indicating excellent uniformity of weight in all the batches of tablet formulations prepared.

All the batches of tablet formulations prepared exhibited good mechanical properties with regard to both hardness and friability. The values are given in Tables 3 & 4. No significant difference in hardness values within the batches of tablet formulations prepared was observed. The friability values of all the batches of tablet formulations prepared are less than 1%.

All the tablet formulations (V-1 to V-4 and O-1 to O-4) prepared by direct compression method fulfilled the compendial requirement of disintegration time for compressed tablets where the times are less than 15 minutes (Tables 3 & 4).

All the tablet formulations were subjected to in vitro dissolution rate studies using phosphate buffer of pH 6.8 as dissolution medium, in order to assess various dissolution characteristics like t_50%, DP₁₅, DE₁₅% and dissolution rate constant values. The corresponding values are given in Tables 5 & 6. and the dissolution profiles are shown in Figs 5 &6.

Formulation	t_50%(min)	DP₁₅ Mean ± SD	DE₁₅ (%) Mean ± SD	K(min^-1) Mean ± SD
V-1	18	45.97 ± 0.76	27.31 ± 0.25	0.033 ± 0.005
V-2	10	66.40 ± 1.03	40.28 ± 0.57	0.094 ± 0.009
V-3	8	71.26 ± 0.70	44.94 ± 0.06	0.090 ± 0.003
V-4	4	98.95 ± 0.45	60.19 ± 0.25	0.276 ± 0.018
DIOVAN^TM 40	6	82.65 ± 0.72	51.42 ± 0.26	0.227 ± 0.036

Formulation	t_50%(min)	DP₁₅ Mean ± SD	DE₁₅ (%) Mean ± SD	K(min^-1) Mean ± SD
O-1	34	29.25 ± 0.86	13.83 ± 0.32	0.013 ± 0.000
O-2	11	59.95 ± 0.71	33.70 ± 0.20	0.144 ± 0.020
O-3	10	68.97 ± 0.70	39.29 ± 0.42	0.155 ± 0.082
O-4	6	99.93 ± 1.03	57.15 ± 0.13	0.268 ± 0.114
OLMY™ 20	6	84.82 ± 1.40	48.62 ± 0.56	0.124 ± 0.004

The t_50% values of V-1, V-2, V-3, V-4 and DIOVAN™ (40mg) tablet formulations are 18, 10, 8, 4 and 6 min respectively. The t_50% values of O-1, O-2, O-3_, O-4 and OLMY™ (20 mg) tablet formulations are 34, 11, 10, 6 and 6 min respectively. Overall, the t_50% values of VAL formulations prepared by direct compression method were in the order V-4 < DIOVAN™ < V-3 < V-2 < V-1 and the t_50% values of OLM formulations prepared by direct compression method were in the order O-4 < OLMY™ < O-3 < O-2 < O-1_.

The DP₁₅ values of V-1, V-2, V-3, V-4 and DIOVAN™ 40mg tablet formulations are 45.97, 66.40, 71.26, 98.95 and 82.65 respectively and V-4 formulation showed higher dissolution rate when compared to V-1, V-2,V-3 formulations and DIOVAN™ (40mg) tablets. The DP₁₅values of O-1, O-2, O-3, O-4 and OLMY™ (20mg) tablet formulations are 29.25, 59.95, 68.97, 99.93 and 84.82 respectively. O-4 tablet formulations showed higher dissolution rate when compared to OLMY™ 20mg, O-1, O-1 and O-3 tablet formulations.

The DE₁₅% values of V-4 formulations are higher when compared to V-1, V-2, V-3 and DIOVAN tablet formulations. A 2.20, 1.49, 1.33 and 1.17 fold increase in DE₁₅% values of V-4 when compared to V-1, V-2, V-3 and DIOVAN™ (40mg) tablet formulations. The DE₁₅% values of O-4 formulations are higher when compared to O-1, O-2, O-3 and OLMY™ 20mg tablet formulations. A 4.13, 1.69, 1.45 and 1.17 fold increase in DE₁₅% values of O-4 when compared to O-1, O-2, O-3 and OLMY (20mg) tablet formulations. Formulations prepared with crospovidone as superdisintegrant showed higher dissolution rates for both VAL (V-4) and OLM (O-4) among other disintegrants ued in the studies. Overall, tablet formulations of recrystallized VAL and OLM products with crosspovidone as super disintegrant showed, superior dissolution properties when compared to drugs alone and marketed products.

Figure 5: Compartive in vitro dissolution profiles of VAL tablet formulations

Figure 6: Comparitive in vitro dissolution profiles of OLM tablet formulations

Accelerated stability studies were carried out for optimized formulations i.e V-4 and O-4 by storing at 40 ± 2⁰ C and 75 ± 5 % RH for three months. Tablets were evaluated for drug content, hardness, friability, and disintegration time and drug percent dissolved at 15 minutes (DP15). From the data obtained, tablets were stable for three months at 40 ± 2⁰ C and 75 ± 5 % RH. The results with regarding to drug content, hardness, friability, disintegration time and DP15 were found to be within the specified limits for both the drug formulations.

Acknowledgements: The authors are thankful to Aurobindo Pharma Ltd (Hyderabad, India) for providing a gift sample of VAL. The authors are also thankful to the Siddhartha Academy of General and Technical Education, Vijayawada, for providing facilities to carry out the research work.

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