Characterization of Melt (Fusion) Solid Dispersions of Nifedipine

Hajare AA*, Shetty YT, Mali MN and Sarvagod SM

Department of Pharmaceutics, Bharati Vidyapeeth, College of Pharmacy, Kolhapur, Maharashtra - 416013.

ABSTRACT

The purpose of this work was to characterize the solid state properties of ternary solid dispersion of hydroxypropylmethylcellulose and Eudragit polymers and a model drug nifedipine by melt (fusion) technique. The solid dispersions were prepared in methanol by heating in water bath maintained at 70°C. Different batches were prepared by using hydroxypropylmethylcellulose K- 4M and Eudragit RS-100 in the concentrations ranging from 0.5 to 4 for one polymer keeping concentration of other polymer constant and vice-versa. Drug excepients interaction study was carried out using Fourier Transform Infra Red spectroscopic technique. The dissolution studies of nifedipine solid dispersions were performed using Apparatus II of USP XXIII in simulated gastric fluid containing 10 % methanol for a period of 10 hours. The aliquots were analysed by using UV-visible spectrophotometer at λmax = 338 nm. The in-process and finished products were evaluated for micromeritic properties. The nature of nifedipine in formulation was studied by powder X- ray diffraction, Fourier transform infra red spectroscopy and differential scanning calorimetry for crystallinity and molecular interaction. The solid dispersion containing HPMC K-4M and Eudragit RS-100 in the ratio of 4:1 showed release only up to 58.99% where as batch (F9) containing 2:1.5 proportion showed 89.10 % release in the 12 hours respectively.

KEY WORDS Solid dispersion, Nifedipine, HPMC K-4M and Eudragit RS-100.

INTRODUCTION:

Nifedipine (4-(2-nitrophenyl)-2, 6-dimethyl -3, 5-dicarbomethoxy-1, 4- dihydropyridine is a calcium channel blocker used in the treatment of a variety of cardiovascular disorders such as angina pectoris and hypertension. It exists in the form of yellow crystals having melting point in the range of 172 – 174°C. Adalat® is a commercially nifedipine product available as an extended-release formulation containing 20 mg.1

Nifedipine has been shown to exist in three monotropically related modifications. Modification-I, m. p. 169 –173°C, is thermodynamically stable at room temperature, modification-II, m. p. 161 –163°C, and modification-III, m. p. 135°C are metastable modifications.2 Four different 1, 4-dioxane solvates (A–D) of nifedipine have also been crystallized and are easily distinguished using calorimetry and infrared spectroscopy.3

Low aqueous solubility of nifedipine often shows lower as well as irregular bioavailability after oral administration.4-5 The improvement of oral bioavailability of poorly water-soluble drugs is one of the most challenging features of drug development. It has been found that solid dispersion of poorly water- soluble drugs in water soluble surface-active and self- emulsifying carriers enhances the drug dissolution as well as bioavailability.6 An ultimate solution to this problem is the reduction of the drug particle size to the very fine or molecular level for rapid dissolution and absorption. The microcrystalline state of the drug in a water-soluble carrier may be achieved by complete solubilization of the desired dose of the drug in the carrier matrix at an elevated temperature followed by crystallization of the drug and possible crystallization of the matrix components on cooling. Hence, the choice of a water-soluble carrier is important in the preparation of a stable solid dispersion.

The preparation and characterization of solid dispersions of nifedipine have been reported by some researchers. The solid dispersions of nifedipine in carriers, such as polyethylene glycol 6000, Polyvinylpyrrolidone, pluronic F68, gelucire have been developed to increase drug absorption.7-8 Solid dispersions of nifedipine in PEG and phosphatidylcholine dissolve faster than the solid drug, which was attributed to the formation of lipid vesicles that entrapped a certain concentration of nifedipine.9 Cogrinding of nifedipine with polyethylene glycol 6000 and hydroxypropyl methylcellulose also improved nifedipine dissolution.10 Solid dispersion of nifedipine in pluronic F68 and gelucire 50/13 (1:1) improved the dissolution of nifedipine compared to the corresponding physical mixture or to the pure drug crystals.11

In this presentation, we report the preparation and characterization of nifedipine solid dispersions in a new polymeric matrix system prepared by using HPMC K-4M and Eudragit RS-100 in the concentration ranging from 0.5% to 4% for one polymer keeping concentration of other polymer constant and vice-versa.12 A preliminary report of the present work was presented as a poster in the PCI sponsored orientation program on current developments in pharmaceutical technology and practice at Sudhakarao Naik Institute of Pharmacy, Pusad.

Figure 1: Molecular structure of nifedipine

The objective of this study are (a) formulation of solid dispersions of nifedipine with variable concentrations of HPMC K- 4M and Eudragit RS-100 (b) to determine the nature of the interactions between nifedipine and the constituents of the polymeric matrix using infrared Fourier transform spectroscopy (c) to study dissolution profile of nifedipine from solid dispersions compared to that of nifedipine alone and (d) to know about physical stability of nifedipine in the optimized matrix systems as a function of time and temperature.

To avoid frequent repetition of some terms and chemical names, we abbreviate them as follows: Hydroxypropylmethylcellulose K-4M (HPMC), Eudragit RS-100 (ERS), Powder X-ray diffraction (PXRD), Infra-red spectroscopy (IR), Furrier transform spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), simulated gastric fluid (SGF), Carr’s compressibility index (CCI) and Hausner’s ratio (HR).

MATERIALS AND METHODS:

Materials:

Nifedipine was obtained as a gift sample from Noveon (Mumbai), Hydroxy propyl methyl cellulose K-4M was provided by Colorcon (Goa) and Eudragit RS-100 by Degussa (Mumbai). Lactose, talc and magnesium Sterate were purchased from S. D. Fine Chemicals (Mumbai) where as all other reagents used were of analytical grade.

Preparation of solid dispersions:

Nifedipine solid dispersions, consisting of various proportions (Table 1) of nifedipine in a mixture of HPMC and ERS matrix system, were prepared by the melt (fusion) method. Powdered ERS was added to methanol and sonicated for 5 minutes for faster solubilization followed by addition of HPMC to have physical mixtures. These mixtures were heated with stirring in water bath maintained at 70°C. To each fused mixture, an appropriate amount of nifedipine and other ingredients were added to produce the desired proportion. These mixtures were stirred for half an hour at same temperature until all the nifedipine dissolves and uniformly disperse in the matrix. The fused mixtures were transferred to porcelain dish and quenched rapidly by placing the dish in an ice bath containing ice and salt. The solidified melts were sieved through sieve number 10 followed by drying for 4 hours in an oven at 40°C. The dried formulations were stored in glass bottles (amber) at room temperature.

Micromeritic study:

The particle size of all formulations was determined by optical microscopy. The derived properties of the solid melts (granules) such as bulk and tapped density, angle of repose, Carr’s compressibility index and Hausner’s ratio values were determined. Kawakita plot was used to analyse the behavior of granules from the bulk density state to the tap density state. The constants ‘a’ and ‘b’ of Kawakita plot were determined from the slope and intercept of graph of n/c versus number of tappings. The reciprocal of slope gives the value of Kawakita constant ‘a’ and from the intercept the value of ‘b’ was obtained.

Powder X-ray diffractometer (PXRD):

PXRD patterns of each of the pure ingredient and all the solid dispersions containing varying proportions of nifedipine in HPMC and ERS matrix were recorded using an X-ray diffractometer (Phillips generator PW-3710, Netherlands) with Ni filtered CuKα line as the source of radiation at a scanning speed of 10°/min at 2θ. The 2θ values and the intensities of the peaks were compared for both pure ingredients and solid dispersed systems.

Infrared Fourier transforms spectra:

The disc method was used to study possible molecular interactions between the drug and polymers. KBr (IR Grade) discs in a proportion of 1:100:: sample: KBr, were prepared and analyzed in FT-IR spectrophotometer (Simadzu FT-IR- 4100, Japan) over a range of 400-4000 cm-1.

Differential scanning calorimetry:

The DSC analysis of nifedipine, physical mixture of drug with polymers and optimized batch was carried out to evaluate any possible drug-polymer interaction. Thermograms were obtained by using Du-Pont DSC, model V4.0B. About 5 mg of sample was weighed in a standard open aluminum pan. An empty pan of the same type was used as a reference. Samples in pan were heated from 50 to 350°C at a heating rate of 10°C/ min, while being purged with dry nitrogen. Calibrations of temperature and heat flow were performed with indium.

Stability studies:

Samples of about 200 mg of each of the solid dispersions were weighed and transferred to air tight amber glass bottles. The bottles were stored in refrigerator (4°C), in stability chamber (45°C) and at room temperature (25°C) for 1 month. Samples were also subjected as unprotected to light at room temperature. After storage under each of these three conditions, the drug content of all the solid dispersions was calculated to compare with the initial amount of drug in dispersions. The drug content was calculated by weighing nifedipine equivalent to 100 mg of each of the solid dispersions and dissolved in 100 ml of methanol. The solution was sonicated for 2 hrs and filter through 0.45µ m membrane filters. The filtrate was then diluted to 10 ml with methanol. The concentration of drug by UV-visible spectroscopic method was determined using UV-visible spectrometer at λmax 338 nm.

Figure 2: Powder X-ray diffraction patterns (PXRD) of nifedipine, HPMC, ERS, and optimized solid dispersion formulation

Solubility measurements:

Solubility measurements were carried out by adding either 20 mg of pure nifedipine or equivalent of solid dispersion, or physical mixture, each containing 20 mg of nifedipine, to 100 ml of SGF containing methanol. As nifedipine is not completely soluble in SGF even at low concentrations, a better solvent, methanol is added to the dissolution medium to maintain sink conditions.

In order to reduce evaporation of the solvent, which may leads to variability of the dissolution results and in addition to provide a more discriminating dissolution medium, a minimal concentration of methanol (10% v/v) was added to the dissolution medium. The suspensions were magnetically stirred at 37°C in a dark room for 48 h, at the end of which samples were withdrawn and filtered through 0.45µ m membrane filters. The filtrates were suitably diluted and analyzed spectrophotometrically at λmax 338 nm. The result of triplicate measurements and their means were calculated.

In-vitro dissolution studies:

The dissolution of Nifedipine was determined using Apparatus II of the USP XXIII. The dissolution medium consisted of SGF (pH 1.2, 0.1 mol/ liter, Hydrochloric acid USP) (without enzymes) containing methanol (10% v/v) maintained at 37 °C. Samples equivalent to 90 mg of nifedipine was added to 900 ml of dissolution medium in a 1000 ml cylindrical vessel. A two-blade stirrer centrally placed at 20 cm from the bottom of the vessel was provided for stirring at 100 rpm. At time intervals of 0.25, 0.5, 0.75, 1.0 hr and then after every 1 hr up to 12 hrs, 5.0 ml samples were withdrawn. The same volume of preheated dissolution medium was infused into the medium after each withdrawal in order to maintain a sink condition. The samples were filtered through Whatman filter paper (pore size 0.45 µm) and the nifedipine content was determined spectrophotometrically at λmax 338nm and drug release were evaluated using linear regression method . All experiments were carried out in triplicate.

Figure 3: Infrared Fourier transform spectra of nifedipine, HPMC, ERS, physical mixture of drug and polymers and optimized formulation

RESULTS AND DISCUSSION: Micromeritic study:

The dispersion of Nifedipine was prepared by melt (fusion) method. The average particle size of prepared dispersions of all batches was found to be in the range of 349 µ m to 437 µ m, bulk densities of all batches were in the range of 0.4012 gm/ml to 0.8277 gm/ml and tapped densities from 0.3378 gm/ml to 0.5250 gm/ml. The flow properties of dispersions are calculated and expressed in terms of Carr’s compressibility index. The batch F3 and F7 shows Carr’s index of more than 20. Carr’s index values less than 20 indicate excellent flow compared to the original crystals. The dispersions with Hausner’s ratio less than 1.18, 1.19-1.25, 1.3-1.5 and greater than 1.5 indicates excellent, good, passable and very poor flow properties respectively. From the Hausner’s ratio calculations it was found that the values varied from 1.05 to 1.66. Lower the value of Hausner’s ratio better is the flow property. All formulations showed excellent to good flow except batch F3. The angle of repose was determined to characterize the dispersions for the frictional resistance for the flow. The flow of the granules was ranked as excellent if the value of angle of repose falls within 25° to 30°. All the batches showed angle of repose within limit for good to excellent flow as determined by fix funnel method. The results of micromeritic study were reported in Table 2.

Kawakita plot is used to analyze the behavior of powder based on ratio of bulk density to the tapped density state. The constant ‘a’ represents the proportion of consolidation as closest packing is attained. The smaller value of ‘a’ indicates good packing even without tapping and ‘b’ represents the packing velocity. The larger value of ‘b’ indicates rapid packing velocity of dispersion compare to corresponding powder. The value for Kawakita analysis was reported in Table 3. From the calculated values of Kawakita plot it was found that majority of the dispersions showed good packing velocity.

Figure 4: DSC of nifedipine, HPMC, ERS, physical mixture of drug and polymers and optimized formulation

Powder X-ray diffraction:

The powder X-ray diffractogram of pure nifedipine, HPMC, ERS and optimized solid dispersion formulation is shown in Fig. 2. Diffractogram of pure nifedipine shows numerous peaks that indicates high crystalline state. The PXRD pattern of the solid dispersion shows characteristic peaks of nifedipine, but of lower intensity and number indicating reduction in crystalline nature of the drug.

Infrared Fourier transforms spectra:

FTIR studies were done to determine any possible interaction between the drug and polymer in solid dispersion. The overlain FTIR spectra of nifedipine, pure polymers, physical mixture of drug with polymers and drug loaded solid dispersions is shown in Fig. 3. The peak of N-H stretching vibration for physical mixture, polymers and pure nifedipine is seen at 3200- 3400 cm-1. The absence of any other peaks in solid dispersion indicates that nifedipine is not undergoing any polymorphic change. By comparing the FTIR spectra of physical mixture with that of solid dispersion it can be concluded that there is no interaction exists between the components of the formulation.

Differential scanning calorimetry:

Differential scanning calorimetric thermograms of nifedipine, nifedipine and polymers, physical mixture of nifedipine and polymer, optimized solid dispersion is shown in Fig 4. Pure nifedipine shows the melting endotherm at 173.3°C. The peaks of drug and individual polymer mixtures as well as that of physical mixture shifts the melting endotherm to lower temperature at about 94.62°C, 58.26°C and 73.60°C for ERS-drug, HPMC-drug and physical mixture at, respectively. No melting endotherm of solid dispersion corresponding to pure nifedipine was observed. It shows the peak at lower temperature at about 142.90°C and hence can be concluded that nifedipine dissolves in polymer completely below the melting temperature of crystalline nifedipine.

Solubility measurements:

The solubility of nifedipine in all forms (pure drug, physical mixture and solid dispersion) was determined in SGF containing methanol. It was found to increase in case of physical mixture by slight amount compared to pure drug whereas it was doubled when formulated as solid dispersion in the SGF containing methanol the results of solubility studies are shown in Table 4. The increase in solubility of nifedipine may be probably due to the formation of soluble complex between the nifedipine and the polymer. It may also be due to improvement of the wetting of the hydrophobic nifedipine crystals in dispersion.

Figure 5: In-vitro drug dissolution profiles of different formulations

Stability study:

Stability data for all batches of solid dispersions at different condition is shown in Table 5. When studied for stability at 4°C, room temperature and at 45°C for a period of month, the drug was found to be stable at all these conditions in a light resistant container; in case of light unprotected conditions the drug was found to be degraded to half of its initial concentration indicating photodegradation.

Table 1: Compositions of nifedipine solid dispersion formulations

Batch code	Nifedipine (mg)	HPMC (mg)	ERS (mg)
F1	20	20	20
F2	20	20	30
F3	20	20	40
F4	20	20	60
F5	20	20	80
F6	20	30	20
F7	20	30	40
F8	20	40	20
F9	20	40	30
F10	20	60	20
F11	20	80	20

In-vitro dissolution studies:

The in-vitro dissolution profiles of the different dispersions in SGF are shown in Fig. 5. Nifedipine release from various dispersion was studied in SGF for a period of 12 hours. Drug release from dispersion of F7 (4:1) was found to be very low (58.99 %) in 12 hours where as F 8 showed highest release for that period. From the in-vitro drug release studies it was found that as the concentration of HPMC increases the drug release decreases. This reveals that drug release from the dispersion was affected by composition and concentration of polymers. The release kinetics of drug is diffusion controlled.

Table 2: Micromeritic study data

Batch Code	Average particle size (µm)	Bulk density (g/cm3)	Tapped density (g/cm3)	CCI	HR	Angle of repose (θ°)
F1	437	0.8277 ± 0.21	0.4966 ± 0.19	40.00 ± 0.9	1.6666 ± 0.5	28.429 ± 1.5
F2	367	0.5006 ± 0.26	0.4417 ± 0.12	11.76 ± 1.2	1.1333 ± 0.6	19.127 ± 1.6
F3	349	0.4517 ± 0.12	0.3840 ± 0.13	15.00 ± 1.2	1.1764 ± 0.6	26.565 ± 1.2
F4	350	0.6132 ± 0.12	0.5050 ± 0.18	17.64 ± 1.2	1.2142 ± 0.5	19.546 ± 1.3
F5	410	0.5356 ± 0.24	0.4285 ± 0.12	20.00 ± 1.5	1.2500 ± 0.3	18.824 ± 1.3
F6	390	0.4190 ± 0.24	0.3688 ± 0.11	12.00 ± 1.3	1.1363 ± 0.4	24.636 ± 1.1
F7	420	0.4012 ± 0.19	0.3378 ± 0.16	15.78 ± 1.3	1.1875 ± 0.2	26.265 ± 1.1
F8	388	0.4800 ± 0.14	0.4137 ± 0.12	13.79 ± 1.4	1.1600 ± 0.3	24.227 ± 1.3
F9	410	0.4666 ± 0.23	0.3855 ± 0.15	17.39 ± 1.4	1.2105 ± 0.2	20.323 ± 1.7
F10	395	0.4864 ± 0.16	0.4500 ± 0.23	05.00 ± 1.6	1.0526 ± 0.2	24.636 ± 1.4
F11	420	0.7000 ± 0.17	0.5250 ± 0.16	25.00 ± 1.8	1.3333 ± 0.5	27.724 ± 1.6

Table 3: Values for Kawakita analysis

Pure nifedipine

6.91 6.75 6.80 6.82

Table 4: Solubility studies of nifedipine

Solid containing

nifedipine

Solubility (µg/ml) at 37 °C in simulated Gastric fluid containing

methanol (10 % v/v)

After 48 h measured

Mean ± S.D

Received on 24.07.2008 Modified on 22.08.2008

Research J. Pharm. and Tech. 1(3): July-Sept. 2008; Page 230-234