Methods to improve dissolution of nitrendipine/Asian Journal of Pharmaceutical Sciences 2008, 3 (3): 102-109

Comparison of methods to improve the dissolution rate of nitrendipine Bengang Youa,b, Na Lianga, Liang Wanga, Fude Cuia, * a

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China b School of Pharmaceutical Science, SooChow University, Suzhou 215007, China Received 16 November 2007; Revised 10 January 2008; Accepted 25 February 2008

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Abstract Purpose: Nitrendipine, a dihydropyridine calcium antagonist, was used as a poorly water-soluble model drug to compare several methods of improving its dissolution rate. Methods: Nitrendipine dispersions were prepared by micronization, solvent deposition, the solvent evaporation method, and the solvent evaporation-deposition method. The drug dissolution rate and the physicochemical properties of these solid dispersions were investigated and compared using dissolution tests, X-ray diffraction analysis (XRD) and differential scanning calorimetry (DSC). Results: The dissolution rate of nitrendipine was greatly improved in disper-sions, particularly in the solid dispersions prepared by the solvent evaporation-deposition method, in which nitrendipine was present in amorphous form and the percentage of nitrendipine dissolved in the first 10 min was more than 80%. Conclusion: The nitrendipine dissolution rate is greatly improved when its solid dispersions were prepared by the solvent evaporation-deposition method. Keywords: Nitrendipine; Solid dispersion; Solvent evaporation-deposition method; Dissolution test _____________________________________________________________________________________________________________

1. Introduction

polymers were used and nitrendipine sustained-release microspheres with a solid dispersion structure were prepared using the spherical crystallization technique [8-10]. The release rate of microspheres could be well controlled and the relative bioavailability of the sustained-release microspheres was significantly improved in dogs. Furthermore, a novel pH-dependent gradient-release delivery system for nitrendipine was also developed. The drug dissolution behavior of the system under the simulated gastrointestinal pH conditions exhibited clear gradientrelease characteristics, and the bioavailability testing suggested that the pH-dependent gradient-release delivery system could markedly improve the uptake of the poorly water-soluble drug and prolong its tmax value in vivo [11,12]. The twin screw extruder method has also been used to prepare nitrendipine–hydroxypropylmethy lcellulosephthalate (HPMC) and nitrendipine–Carbopol solid dispersions, and the nitrendipine–Carbopol system was found to exhibit a higher dissolution rate than crystalline nitrendipine, physical mixtures, and the nitrendipine–HPMC system [13]. The purpose of the present study is to improve the in vitro dissolution rate of nitrendipine and to compare typical methods used to prepare nitrendipine solid dispersions. Four methods, micronization, solvent deposition,

With the recent increase in the high throughput screening of potential therapeutic agents, the number of poorly water-soluble drug candidates has risen sharply and the formulation of poorly water-soluble compounds for oral delivery is now one of the most frequent and greatest challenges for formulation scientists in the pharmaceutical industry. During the past 40 years, various approaches have been used to improve the in vitro dissolution rate and in vivo bioavailability of poorly water-soluble drugs, such as salt formation, solubilization, particle size reduction including micronization [1] and grinding/co-grinding [2], solvent deposition [3], and the preparation of solid dispersions [4]. Nitrendipine, a dihydropyridine calcium channel antagonist [5-7], is a typical poorly water-soluble drug and is often selected as a model drug to improve the in vitro dissolution rate and in vivo bioavailability because of its very low solubility. To improve the bioavailability of nitrendipine, solid dispersing and sustained-release __________ *Corresponding author. Address: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China. Tel.: +86-24-23986353; Fax: +86-24-23986355. E-mail: [email protected]

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Methods to improve dissolution of nitrendipine/Asian Journal of Pharmaceutical Sciences 2008, 3 (3): 102-109

2.2.2. Solvent evaporation method

the solvent evaporation method, and the solvent evaporation-deposition method which combined the solvent deposition method and the solvent evaporation method, were used to prepare nitrendipine solid dispersions and compared using the dissolution test; the state of the drug in the solid dispersions was also examined and compared by XRD and DSC.

Physical mixtures of the drug and water-soluble carrier at a weight ratio of 1: 5 for a binary system were dissolved in the mixed solvent of ethanol and dichloromethane (1/2, v/v). After complete dissolution, the mixed solvent was removed using a rotary evaporator and samples were subsequently dried in a vacuum oven at 40˚C for 24 h. After crushing, the solid dispersions less than 80 mesh (210 μm) were selected and stored desiccated at 4–8˚C and protected from light.

2. Materials and methods 2.1. Chemicals and reagents

2.2.3. Solvent deposition method

Nitrendipine (NTD, Nanjing Pharmaceutical Factory, China) was used as a water insoluble model drug. Polyvinyl pyrrolidone K-30 (PVPk30, ISP), Pluronic F68 (F68, ISP) and polyethylene glycol 4000, 6000 (PEG4000, 6000, Fluka) were used as water soluble carriers. Microcrystalline cellulose (MCC, Asahi Kasei Corporation, Japan), light anhydrous silicic acid (Aerosil, Guangzhou People Chemical Plant, China), lactose (Tianjin Chemical Plant, China) and low substituted hydroxypropyl cellulose (L-HPC, Huzhou Zhanwang Pharmaceutical Co. Ltd., China) were used as waterinsoluble carriers. Sodium dodecyl sulfate (SDS) was added to the dissolution medium to improve the wetting of the solid dispersions and to ensure that the drug had dissolved completely. It was found that the solution of ethanol and dichloromethane mixed in a suitable ratio was a good solvent for dissolving both nitrendipine and water-soluble carriers. All other chemicals were of analytical grade.

Drug was dissolved in the mixed solvent of ethanol and dichloromethane (1/2, v/v), and a water-insoluble carrier (1: 5 drug: carrier weight ratio) was then added. After complete mixing, the solvent was evaporated in a water bath at 80˚C, and the deposits were subsequently dried, crushed, selected and stored as before. 2.2.4. Solvent evaporation-deposition method Physical mixtures of drug and water-soluble carrier at a weight ratio of 1: 2 were dissolved in the mixed solvent of ethanol and dichloromethane (1: 2, v/v). After complete dissolution, water insoluble carrier at a 1: 5 drug: carrier weight ratio was added. After the ternary systems had been completely mixed, the solvent was evaporated in a water bath at 80˚C, and the solid dispersions were subsequently dried, crushed, selected and stored as before.

2.2. Sample preparation 2.3. Dissolution test 2.2.1. Micronization Drug dissolution tests on the solid dispersions prepared as described above were carried out for 60 min at 100 r/min by the paddle method as specified in the Ch. P. 2000ed. The temperature of the dissolution medium was controlled at 37 ± 0.5˚C. The solid dispersions were weighed to be equivalent to 20 mg nitrendipine. The dissolution medium was 900 ml distilled water containing

Nitrendipine, and a physical mixture of nitrendipine and PVPk30 at a weight ratio of 1: 2 for a binary system were both micronized. After drying in a vacuum oven at 40˚C for 24 h, the powdered drug and mixtures in the range of 500–800 nm were selected and stored desiccated at 4–8˚C and protected from light.

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Methods to improve dissolution of nitrendipine/Asian Journal of Pharmaceutical Sciences 2008, 3 (3): 102-109

SDS (0.3%, w/v) to ensure that the drug be dissolved completely and the dissolution profiles of the solid dispersions could be clearly distinguished from each other. Five milliliters of the dissolution medium was sampled at selected intervals, and replaced with fresh dissolution medium to keep the volume constant. The withdrawn sample was passed through a membrane filter (0.8 mm), and the filtrate was assayed spectrophotometrically at 358 nm to determine the dissolved drug concentration using a spectrophotometer (Mode 752, Shanghai the Third Analytical Instrument Plant, China).

rates of the drug from the dispersions were increased markedly. In the case of the nitrendipine depositions prepared by the solvent deposition method, the drug was dispersed completely on the surface of the water-insoluble carriers and might be present in a microcrystalline state or very fine particles. Once the depositions were exposed to aqueous media, because of the greatly enhanced surface area, the dissolution rate of the drug would be increased greatly (Fig. 3 and Fig. 4). In the case of the binary systems prepared by the solvent evaporation method and the solvent deposition method, the dissolution rates of drug were associated with the types of water-soluble carriers in the solid dispersions and the water-insoluble carriers in the depositions, for which the rank order of dissolution was PVPk30 > F68 > PEG6000 > PEG4000 (Fig. 2) for water-soluble carriers and L-HPC > MCC > lactose >  Aerosil (Fig. 3) for water-insoluble carriers. This might be attributed to the differences in their hydrophilicity. As shown in Fig. 1–4, the dissolution rates of nitrendipine from dispersions prepared by the four methods were all increased greatly, although the amount of drug dissolved depended to a large extent on the carriers and methods. The dissolution rate of drug from ternary systems prepared by the solvent evaporation-deposition method was faster than from binary systems prepared by the solvent deposition method or the solvent evaporation method. This might be associated with the ratio of drug to carriers and the state of the drug in the dispersions.

2.4. X-ray diffraction analysis Powder XRD patterns were determined with a diffractometer (Geigerflex RAD-IB, Rigaku, Tokyo). The operating conditions were as follows: target, Cu; filter, Ni; voltage, 40 kV; current, 20 mA and scanning speed, 2θ = 4˚/min. 2.5. Differential scanning calorimetry DSC curves were determined with a DSC instrument (DSC-7, Perkin-Elmer, Norwalk, CT, USA). The heating rate was 4˚C/min and the rate of nitrogen gas flow was 70 ml/min.

3. Results and discussion 3.1. Drug dissolution profiles A higher dissolution rate of nitrendipine was obtained when the drug was micronized to 500–800 nm, and this was attributed to the reduction in particle size of the drug and the increased surface area available for dissolution (Fig. 1). The water-soluble carrier was able to modify the surface properties of the drug, resulting in a reduction in the contact angle value as well as an improvement in the wettability of the powder, leading to an increase in the dissolution rate. As shown in Fig. 1, the amount of drug dissolved from the micronized mixture of drug and PVPk30 was somewhat higher than from the micronized drug alone and Fig. 2 and Fig. 4 show that the dissolution

3.2. Comparison of dissolution profiles and preparation methods Although particle size reduction is commonly used to increase the dissolution rate, there is a practical limit to how much reduction can be achieved by commonly used methods such as controlled crystallization, grinding, and micronization. The use of very fine powders in a dosage form may also be problematic because of handling difficulties and poor wettability. According to the results of the dissolution tests on the nitrendipine samples, it was concluded that solid

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Methods to improve dissolution of nitrendipine/Asian Journal of Pharmaceutical Sciences 2008, 3 (3): 102-109

100 90 80

Percent released (%)

70 60 50

500-800 nm NTD

40

500-800 nm mixture

30

original NTD

20 10 0 0

10

20

30

40

50

60

Time (min) Fig. 1. Dissolution profiles of nitrendipine micronized powders (n = 6).

100

Percent released (%)

80

60 PEG4000 PEG6000 PVPk30 F68 NTD

40

20

0 0

10

20

30

40

50

60

Time (min) Fig. 2. Dissolution profiles of nitrendipine solid dispersions prepared by the solvent evaporation method (n = 6).

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100

MCC Aerosil Lactose L- HPC NTD

Percent released (%)

80

60

40

20

0 0

10

20

30

40

50

60

Time (min) Fig. 3. Dissolution profiles of nitrendipine depositions (n = 6).

100

Percent released (%)

80

60 PVPk30 + Aerosil PEG6000 + HPC

40

Px188 + MCC NTD

20

0 0

10

20

30

40

50

60

Time (min) Fig. 4. Dissolution profiles of nitrendipine solid dispersions prepared by the solvent evaporation-deposition method (n = 6).

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dispersions for a ternary system composed of nitrendipine, PVPk30 and L-HPC would have a higher dissolution rate. Therefore, a nitredipine solid dispersion composed of nitrendipine, PVPk30 and L-HPC at a weight ratio of 1: 2: 7 was prepared by the solvent evaporation-deposition method, a physical mixture with the same composition was prepared by simple mixing, and a binary system of drug/L-HPC (1/9) deposition was also prepared by the solvent deposition method. Dissolution tests showed that in the case of the solid dispersion prepared by the solvent evaporation-deposition method the percentage of drug dissolved within the first 10 min was more than 80%, and the drug dissolution rate was markedly improved and clearly higher than that obtained by other methods (Fig. 5). Compared with the other methods, the advantages of the solvent evaporation-deposition method were as follows: firstly, drug could be dispersed more completely than micronization and the solvent deposition method, as shown in Fig. 6 and Fig. 7, and the drug in the solid dispersion might be in an amorphous or molecular state, which would contribute to a higher dissolution rate; secondly,

drug and water soluble carriers were deposited equally on the surface of the water insoluble carriers when the solvent was evaporated, and the viscosity of the solution of drug and water-soluble carriers would be markedly decreased and the organic solvent could be removed easily and completely, making the process faster and simpler than the solvent evaporation method [14]; thirdly, the physicochemical properties of the water insoluble carriers showed that they were stable and biologically inert, and the effect of temperature and humidity on the drug would be reduced or avoided when the drug and water-soluble carriers were dispersed uniformly in-water insoluble carriers, which would enhance the physicochemical stability of the nitrendipine solid dispersion. 3.3. State of nitrendipine in solid dispersions As can be seen in Fig. 6, the XRD pattern of micronized powders was similar to pure nitrendipine, which was consistent with the results of DSC (Fig. 7), indicating that the crystallinity of the drug was not changed by

100

Percent released (%)

80 A B C D E F G

60

40

20

0 0

10

20

30

40

50

60

Time (min) Fig. 5. Dissolution profiles of nitrendipine dispersions prepared by different methods (n = 6). A, original crystals of nitrendipine; B, PVPk30; C, L-HPC; D, physical mixtures (nitrendipine: PVPk30: L-HPC = 1: 2: 7); E, 500–800 nm mixtures (nitrendipine: PVPk30 = 1: 2); F, nitrendipine depositions (nitrendipine: L-HPC = 1: 9); G, nitrendipine solid dispersions prepared by the solvent evaporation method (nitrendipine: PVPk30 = 1: 5); H, nitrendipine solid dispersions prepared by the solvent evaporation-deposition method (nitrendipine: PVPk30: LHPC = 1: 2: 7).

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8000 7000

A

Intensity (Counts)

6000

B

5000

C

4000

D

3000

E

2000

F

1000

G

0 5

10

15

20

25

30

35

40

2© (̓) Fig. 6. X-ray powder diffractograms of nitrendipine dispersions. A, original crystals of nitrendipine; B, PVPk30; C, L-HPC; D, physical mixtures (nitrendipine: PVPk30: L-HPC = 1: 2: 7); E, 500–800 nm mixtures (nitrendipine: PVPk30 = 1: 2); F, nitrendipine depositions (nitrendipine: L-HPC = 1: 9); G, nitrendipine solid dispersions prepared by the solvent evaporation method (nitrendipine: PVPk30 = 1: 5); H, nitrendipine solid dispersions prepared by the solvent evaporation-deposition method (nitrendipine: PVPk30: LHPC = 1: 2: 7).

A

DSC (PW)

0 -15000 0 -3000 0 -3000 0

B C D

-2500 0

E

-2500 0

F

-2500 0

G

-2000 0

H

-3000 0

50

100

150

200

Temperature (̓C) Fig. 7. DSC thermograms of nitrendipine dispersions. A, original crystals of nitrendipine; B, PVPk30; C, L-HPC; D, physical mixtures (nitrendipine: PVPk30: L-HPC = 1: 2: 7); E, 500–800 nm mixtures (nitrendipine: PVPk30 = 1: 2); F, nitrendipine depositions (nitrendipine: L-HPC = 1: 9); G, nitrendipine solid dispersions prepared by the solvent evaporation method (nitrendipine: PVPk30 = 1: 5); H, nitrendipine solid dispersions prepared by the solvent evaporation-deposition method (nitrendipine: PVPk30: LHPC = 1: 2: 7).

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References

micronization. Some small crystalline peaks of nitrendipine could still be found in physical mixtures and depositions, although the relative intensity of most peaks corresponding to drug was lower than that of nitrendipine alone, suggesting the presence of a small quantity of nitrendipine crystals in mixtures and depositions. These results show that nitrendipine can be highly dispersed by deposition because of the increase in surface area and a reduction in particle size, but not the transformation of crystallinity. No crystalline peaks of nitrendipine were observed in solid dispersions prepared by the solvent evaporation method and the solvent evaporation-deposition method, suggesting that nitrendipine crystals were converted to an amorphous or a molecular form in these systems during the production process [15]. Fig. 7 shows characteristic thermograms of pure nitrendipine, PVPk30 and L-HPC, and the binary and ternary systems. The pure nitrendipine curve showed an endothermic peak at about 157.1˚C, and this corresponded to the melting point of nitrendipine. Only a broad peak could be observed in PVPk30 and L-HPC curves below 100˚C. There was no appreciable shift in the melting peak of nitrendipine in the micronized powders, physical mixtures and depositions, indicating a crystalline fraction in these systems, which was in agreement with the results of XRD. Because of the amorphous structure of the solid dispersions, no melting point peak was observed in the thermograms.

[1] G. G. Liversidge, K. C. Cundy. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int. J. Pharm., 1995, 125: 91-97. [2] K. Itoh, A. Pongpeerapat, Y. Tozuka, et al. Nanoparticle formation of poorly water-soluble drugs from ternary ground mixture with PVP and SDS. Chem. Pharm. Bull., 2003, 51: 171-174. [3] S. L. Law, C. H. Chiang. Improving dissolution rates of griseofulvin by deposition on disintegrants. Drug Dev. Ind. Pharm., 1990, 16: 137-147. [4] A. T. M. Serajuddin. Solid dispersion of poorly watersoluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm Sci., 1999, 88: 1058-1066. [5] B. P. Bean, M. Sturek, A. Puga, et al. Nitrendipine block of calcium channels in cardiac and vascular muscle. J. Cardiovasc. Pharmacol., 1987, 9: S17-S24. [6] S. R. F. Filho, M. A. Saragoca, P. C. Oliveira, et al. Use of nitrendipine in the treatment of systolic hypertension in elderly patients. J. Cardiovasc. Pharmacol., 1987, 9: S218-S220. [7] F. H. Messerli, R. E. Schmieder, H. O. Ventura, et al. The effect of nitrendipine on systemic hemodynamics in essential hypertension. J. Cardiovasc. Pharmacol., 1987, 9: S178-S181. [8] M. S. Yang, F. D. Cui, B. G. You, et al. Preparation of sustained-release nitrendipine microspheres with Eudragit RS and Aerosil using quasi-emulsion solute diffusion method. Inter. J. Pharm., 2003, 259: 103-113. [9] M. S. Yang, F. D. Cui, Y. Fan, et al. Effect of three types of additives in poor solvent on preparation of sustainedrelease nitrendipine microspheres by the quasi-emulsion solvent diffusion method. J. Drug Deliv. Sci. Technol., 2005, 15: 129-135. [10] F. D. Cui, M. S. Yang, Y. Y. Jiang, et al. Design of sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion solvent diffusion method. J. Control. Release, 2003, 91: 375-384. [11] M. S. Yang, F. D. Cui, B. G. You, et al. A novel pHdependent gradient-release delivery system for nitrendipine I. Manufacturing, evaluation in vitro and bioavailability in healthy dogs. J. Control. Release, 2004, 98: 219-229. [12] Ming-shi Yang, Fu-de Cui, Bengang You, et al. A novel pHdependent gradient-release delivery system for nitrendipine II. Investigations of the factors affecting the release behaviors of the system. Int. J. Pharm., 2004, 86: 99-109. [13] L. Wang, F. D. Cui, T. Hayase, et al. Preparation and evaluation of solid dispersion for nitrendipine-carbopol and nitrendipine-HPMCP systems using a twin screw extruder. Chem. Pharm. Bull., 2005, 53: 1240-1245. [14] C. Leuner, J. Dressman. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm., 2000, 50: 47-60. [15] C. Leuner, J. Dressman. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm., 2000, 50: 47-60.

4. Conclusions The results obtained show that the nitrendipine dissolution rate could be markedly improved by micronization, deposition and solid dispersion preparation, especially using the solvent evaporation-deposition method. Compared with micronization, deposition and the solvent evaporation method, the solvent evaporation-deposition method had more advantages because of the increased surface area and the presence of drug in an amorphous form, which results in a higher drug dissolution rate in vitro and, subsequently, a better in vivo oral bioavailability for poorly water-soluble drugs.

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