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Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method
Powder Technology 141 (2004) 187 – 195 www.elsevier.com/locate/powtec
Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method Hirofumi Takeuchi, Shinsuke Nagira, Hiromitsu Yamamoto, Yoshiaki Kawashima * Department of Pharmaceutical Engineering, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan Available online 27 April 2004
Abstract Solid dispersion particles of tolbutamide (TBM) were prepared by formulating nonporous (Aerosil 200 (hydrophilic), Aerosil R972 (hydrophobic)) or porous (Sylysia 350 (hydrophilic), Sylophobic 200 (hydrophobic)) silica as a carrier and applying the spray-drying (SD) or evaporation (Eva) method. In the solid dispersion particles prepared by the SD method, TBM existed in a meta-stable form (Form II) irrespective of the type of silica. On the other hand, when the Eva method was used, various crystalline forms of TBM were observed in the solid dispersion particles according to the type of silica. Polymorphs of Forms III and IV were prepared with Aerosil 200 and Aerosil R972, respectively, while crystalline Form II was obtained when either of the forms of porous silica, Sylysia 350 or Sylophobic 200, was formulated. The dissolution property of TBM in the solid dispersion particles prepared with hydrophilic silica was remarkably improved compared with those of the original TBM crystals (Form I) or spray-dried TBM without silica (Form II). In the case of hydrophobic silica, the release rate of TBM from the solid dispersion particles was much slower than that of original TBM. The meta-stable form of TBM in the solid dispersion particles was stable for at least 4 weeks when stored at 60 jC and 0% RH, while the spray-dried TBM without silica (Form II) was gradually converted to the stable form (Form I) under the same storage conditions. Under the humid storage conditions (60 jC, 75% RH), the spray-dried TBM without silica (Form II) immediately converted into the stable form (Form I) within 1 day, while TBM (Form II) in the solid dispersions in a matrix of silica was stable for at least 1 week. D 2004 Elsevier B.V. All rights reserved. Keywords: Tolbutamide; Polymorphs; Solid dispersion particle; Porous silica; Spray-drying
1. Introduction Improvement of the dissolution property of pharmaceuticals is extremely important, especially since the percentage of drugs with poor water solubility has increased in recent years. Various methods have been reported to improve the dissolution property of drugs, such as grinding, formation of inclusion compound with cyclodextrin, and solid dispersion with water soluble polymers. According to the Noyes – Whitney equation [1], the dissolution rate of a drug depends on its surface area and solubility. It is easier to increase the surface area by reducing the particle size of drug crystals than to increase the drug solubility. The particle size may be easily reduced by simple grinding. However, the ground crystals tend to agglomerate, thereby creating a surface with higher energy than that of the original crystals, and reducing the effective surface area for dissolution. * Corresponding author. Tel.: +81-58-237-3931; fax: +81-58-237-6524. E-mail address: [email protected] (Y. Kawashima). 0032-5910/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2004.03.007
Solid dispersion is a useful method to disperse drugs in the molecular state in a carrier matrix [2,3]. The interaction between the drug molecule and carrier is responsible for drug dispersion, and may depress the crystallization of drug in the prepared system. The most popular carrier materials are water soluble polymers such as PEG [4] or PVP [5]. However, it is often complained that drugs prepared by solid dispersion with a water-soluble polymer carrier tend to be sticky or tacky. This property leads to a decrease in the recovery of solid dispersion in preparation and also to difficulty of handling in the subsequent processes. Milling or mixing with other excipients is required before preparing the final dosage forms by plugging into capsules or tabletting. These processes sometimes facilitate crystallization of the drug in an amorphous state in the solid dispersion. The change in the crystalline forms of drug in the dosage form affects its bioavailability after administration. The spray-drying technique is a useful method to obtain spherical particles which have small size and narrow distribution. This method also has the advantage that granulation
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and drying are completed in one step. In a previous paper [6], we demonstrated that solid dispersion particles of a poorly water soluble drug, tolbutamide (TBM), could be prepared by spray-drying the drug solution with a nonporous silica, Aerosil 200. It was also confirmed that the drug was molecularly dispersed in the matrix formed with silica particles. The resultant solid dispersion particles were freely flowing and remarkably improved the dissolution property of the drug. Silicas having many silanol groups on their surfaces may be able to form hydrogen bonds with drug molecules [7]. There are two types of silica, porous and nonporous. Several grades of silica particle having different properties, such as particle size, degree of hydrophilicity, and pore structure, are available for both types. In the pharmaceutical field, other porous materials, such as calcium silicate [8,9], controlled pore glass [10,11], and porous cellulose [12], are also used to formulate solid dosage forms. It has been pointed out that the porous structure itself confers special characteristics, such as a decrease of melting point and a decrease in the crystallinity of drugs entrapped in the pores [10 – 13]. Thus, a porous silica is expected to be successfully applied to the solid dispersion formulation as its carrier material. TBM, which is used in this study as a model drug, is a poorly water soluble drug for diabetics. Four types of polymorph (types I, II, III, and IV) have been reported for TBM [14], and the dissolution, bioavailability, and stability of these polymorphs have been investigated by Kimura et al. [15,16]. In the present study, we investigated the solid dispersion particles prepared by spray-drying an ethanol solution of TBM with several colloidal silica having different physicochemical properties, e.g., different particle structures and hydrophilicities. The effect of the properties of the carrier particles on the polymorphs and dissolution property of drug in solid dispersions was examined. The stability of the metastable crystalline form of the drug in storage was also tested.
Table 2 Particle size of solid dispersion particles prepared by the SD method Sample
Particle size (Am) D16
D50
D84
Original TBM Spray-dried TBM SD solid dispersion with Aerosil 200 SD solid dispersion with Sylysia 350 SD solid dispersion with Aerosil R972 SD solid dispersion with Sylophobic 200
15.4 F 0.6 6.4 F 0.3 2.4 F 0.3
28.7 F 0.5 11.6 F 0.6 5.6 F 0.1
48.9 F 1.6 18.4 F 1.6 8.8 F 1.6
1.7 F 0.0
3.2 F 0.0
5.2 F 0.0
1.7 F 0.1
3.7 F 0.1
6.4 F 0.2
1.7 F 0.1
3.1 F 0.1
5.0 F 0.3
The data are the average values of four runs.
Aerosil, Japan; Sylysia 350 and Sylophobic 200 from Fuji Silysia, Japan) were used as obtained. Aerosil 200 and Aerosil R972 are nonporous forms of silica, and Sylysia 350 and Sylophobic 200 are porous forms. Aerosil 200 and Sylysia 350 are hydrophilic and Aerosil R972 and Sylophobic 200 are hydrophobic. Sylophobic 200 was prepared by introducing a hydrophobic moiety into Sylysia 350 in the preparation process. The properties of the silicas used are shown in Table 1. The data were obtained from the catalogs of the suppliers. We also measured the particle size of Sylysia 350 and Sylophobic 200 using a laser diffraction size analyzer (LDSA-2400A; Tonichi-Computer, Japan) in combination with a powder dispersion instrument (PD-10S; Tonichi-Computer). The specific surface area of silica was also measured by the N2 adsorption method (Gemini; Shimadzu) after degassing the sample powder at 40 jC overnight (Flow Prep060; Shimadzu). The values shown in parenthesis in Table 1 confirmed the validity of the values in the catalogs. All other chemicals and solvents were of reagent grade. 2.2. Preparation of solid dispersion particles
2. Experimental 2.1. Materials TBM was a gift from Aventis Pharma, Japan. Several types of silica (Aerosil 200 and Aerosil R972 from Nihon
Solid dispersion particles of TBM with fine silica particles were prepared using two different methods of solvent removal: the spray-drying (SD) method and the evaporation (Eva) method. For the preparation of solid dispersion particles by the SD method, 1.0 g of silica was suspended in 50.0 ml of ethanol solution into which 1.0 g of TBM had
Table 1 Physicochemical properties of Aerosil 200, Aerosil R972, Sylysia 350 and Sylophobic 200 Sample
Porous or nonporous
Hydrophilic or hydrophobic
Particle size (Am)
Specific surface area (m2/g)
Pore size (nm)
Pore volume (ml/g)
Aerosil 200 Aerosil R972 Sylysia 350 Sylophobic 200
Nonporous
Hydrophilic Hydrophobic Hydrophilic Hydrophobic
0.012 0.016 3.9 (3.3 F 0.1) 3.9 (3.0 F 0.1)
200 (193.2 F 0.9) 110 300 (251.3 F 1.5) N.D.
21.0 N.D.
1.60 N.D.
Porous
N.D.: not determined. The values were obtained from the catalog of Aerosil (Nihon aerosil) or Sylysia. (Fuji silysia). The values measured in the present study are given in parenthesis.
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Fig. 1. Observation of solid dispersion particles of tolbutamide with Aerosil 200 or Sylysia 350 prepared by the SD or Eva method. (A) Aerosil 200;(B) Sylysia 350; (C) SD solid dispersion with Aerosil 200; (D) SD solid dispersion with Sylysia 350.
been dissolved. This suspension was fed to a spray dryer (GS31; Yamato, Japan) at rate of 10 ml/min and sprayed into the chamber from a nozzle with a diameter of 406 Am at a pressure of 0.12 to 0.15 MPa. The inlet and outlet temperatures of the drying chamber were maintained at 100 and 70 jC, respectively. The spray-dried TBM particles
were prepared from the ethanol solution of TBM under the same conditions. In the preparation by the Eva method, 0.5 g of silica was suspended in 25.0 ml of ethanol solution into which 0.5 g of TBM had been dissolved. This suspension was evaporated in an evaporator (N-2NW; EYELA, Japan) with a rotation speed of 4 rpm at 60 jC for 25 min. The
Fig. 2. Powder X-ray diffraction patterns of original TBM crystals, spray-dried TBM crystals, and evaporated TBM crystals. (A) Original TBM crystals; (B) spray-dried TBM; (C) evaporated TBM.
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Table 3 Crystalline form of original TBM crystals, spray-dried TBM, evaporated TBM and TBM in solid dispersion particles Preparation method
Silica
Crystalline form
SD
– Sylysia 350 Aerosil 200 Sylophobic 200 Aerosil R972 – Sylysia 350 Aerosil 200 Sylophobic 200 Aerosil R972
II II II II II I II III II IV
Eva
resultant solid dispersion in a flask was softly ground by a mortar and pestle. All solid dispersion particles were dried in a desiccator with blue silica gel under reduced pressure for 1 day before testing their physicochemical properties.
medium (pH 6.8) for a disintegration test with paddle stirring at a rotation speed of 100 rpm at 37 jC, as specified in JPXIV. The drug concentration in the medium was measured spectrophotometrically at 226 nm (UV-160A; Shimadzu, Japan). 2.5. Stability test Sample particles were stored in desiccators with 0% RH (P2O5 powder) or 75% RH (Saturated solution with NaCl) at 60 jC. The crystalline form of TBM in solid dispersion particles was measured by the powder X-ray diffraction method (RAD-IC; Rigaku) at appropriate time intervals.
3. Results 3.1. Physicochemical properties of solid dispersion particles
2.3. Physicochemical property of solid dispersion particles The size of solid dispersion particles was measured by a laser diffraction size analyzer (LDSA-2400A; Tonichi-Computer, Japan). The particle shape was observed by scanning electron microscopy (JSM-T330A; Nihon Denshi, Japan). The crystalline form of TBM in solid dispersion particles was measured by the powder X-ray diffraction method (RAD-IC; Rigaku Denki, Japan). 2.4. Dissolution test The dissolution test was carried out according to Japanese Pharmacopoeia XIV. Sample (25 mg of TBM or 50 mg of solid dispersion particles) was added to 900 ml of No. 2
Table 2 lists the particle size of spray-dried TBM and TBM solid dispersion particles prepared by the spray-drying method (SD solid dispersion). The particle size of spraydried TBM and TBM solid dispersion particles was smaller than that of original TBM crystals. The type of silica did not affect the size of the resulting solid dispersion particles. It was characterized that the particle size was comparable to that of original Sylysia 350 or Sylophobic 200 particles. This fact suggested that the drug molecules or crystals were well dispersed on the surface of the porous silica particles to form the solid dispersion particles. On the other hand, the particle size of SD solid dispersion particles prepared with nonporous silica was much larger than that of the silica particles shown in Table 1. It means that the SD solid
Fig. 3. Powder X-ray diffraction patterns of TBM in solid dispersion particles with Aerosil 200 or Sylysia 350 prepared by the SD or Eva method. (A) SD solid dispersion with Aerosil 200; (B) SD solid dispersion with Sylysia 350; (C) Eva solid dispersion with Aerosil 200; (D) Eva solid dispersion with Sylysia 350.
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Fig. 4. Powder X-ray diffraction patterns of TBM in solid dispersion particles with Aerosil R972 or Sylophobic 200 prepared by the SD or Eva method. (A) SD solid dispersion with Aerosil R972; (B) SD solid dispersion with Sylophobic 200; (C) Eva solid dispersion with Aerosil R972; (D) Eva solid dispersion with Sylophobic 200.
dispersion particles are the agglomerates of the nonporous silica particles. The size of solid dispersion particles prepared by the evaporation method (Eva solid dispersion) may depend on the grinding conditions. The mass of solid dispersion particles prepared with Aerosil 200 was so hard that it could not be ground into fine particles under soft grinding conditions (D50: 22.5 F 0.92 Am). On the other hand, the mass of solid dispersion particles prepared with Sylysia 350 was
soft and easily ground. The average particle size (D50) of the resulting solid dispersion particles was 4.29 F 0.16 Am, which was almost comparable to that of the original Sylysia 350 particles or the solid dispersion particles prepared by spray-drying. This result suggested that the same solid dispersion particles with Sylysia 350 could be prepared using either preparation method. The SEM photographs of these particles are shown in Fig. 1. It was confirmed that Aerosil 200 particles formed
Fig. 5. Dissolution profile of TBM from solid dispersion particles with Aerosil 200 or Sylysia 350 prepared by the SD or Eva method. : Original TBM crystals; .: Spray dried TBM; E: SD solid dispersion with Aerosil 200; n: SD solid dispersion with Sylysia 350; D: Eva solid dispersion with Aerosil 200; 5: Eva solid dispersion with Sylysia 350.
Fig. 6. Dissolution profile of TBM from solid dispersion particles with Aerosil R972 or Sylophobic 200 prepared by the SD or Eva method. : Original TBM crystals; E: SD solid dispersion with Aerosil R972; n: SD solid dispersion with Sylophobic 200; D: Eva solid dispersion with Aerosil R972; 5: Eva solid dispersion with Sylophobic 200.
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Table 4 Stability of the crystalline form of TBM in solid dispersion particles stored at 0% or 75% RH and 60 jC Preparation method
SD
SD
Silica
–
Aerosil 200
Sylysia 350
Aerosil 200
Sylysia 350
Initial (days)
II
II
II
III
II
1 7 14 21 28 1 7 14 21
I + II I + II I + II I + II I I I I I
II II II II II II II I + II I + II
III III I + III I + II I + III III I + III I I
28
I
I + II
II II II II II II II II Hallo pattern Hallo pattern
II II II II II II II II Halo pattern Hallo pattern
0% RH 60 jC
75% RH 60 jC
Eva
I
agglomerates and the SD solid dispersion particles with Aerosil 200 were smaller than the agglomerates of Aerosil 200. As confirmed by particle size measurement, there was little difference between the Sylysia 350 particles and SD solid dispersion particles sprayed with Sylysia 350. 3.2. Crystalline form of TBM in solid dispersion particles Powder X-ray diffraction patterns of original TBM crystals and TBM particles prepared by spray-drying or evaporating the ethanol solution of TBM are shown in Fig. 2. The crystalline form of spray-dried TBM was meta-stable (Form II), while evaporated TBM took the same crystalline form as the original TBM crystals, i.e., the stable form (Form I). This result suggested that the evaporation rate of
solvent affected the resultant crystalline form. The rapid evaporation rate in spray-drying may facilitate the formation of the meta-stable form. Table 3 summarizes the crystalline forms of TBM in SD or Eva solid dispersion particles prepared with various types of silica. In the case of solid dispersion particles prepared by the SD method, the crystalline form of TBM in solid dispersion particles was meta-stable (Form II), which was also the form of the spray-dried TBM without silica. However, in the Eva method, various crystalline forms of TBM, including Type III and IV, were detected depending on the type of the silica particles formulated. When Sylysia 350 or Sylophobic 200 particles were formulated, the metastable form (Form II) of TBM was obtained. Because these silica particles have similar pore structures, the pores seemed to be responsible for formation of the meta-stable crystalline Form II under the evaporation conditions. The powder X-ray diffraction patterns of the typical samples are shown in Figs. 3 and 4. 3.3. Dissolution property of TBM in solid dispersion particles The dissolution profiles of TBM from the various solid dispersion particles were measured (Figs. 5 and 6). All solid dispersion particles with hydrophilic silica remarkably improved the dissolution rate of TBM compared with original TBM crystals (Fig. 5). The meta-stable TBM particles prepared by spray-drying the drug solution without formulating the silica particles (Form II) also improved the dissolution property, but the dissolution was still lower than that by solid dispersion. This result implied that the hydrophilic property of the silica particles contributed to the improved drug dissolution from the solid dispersion. The solid dispersion particles sprayed with Aerosil R972 or Sylophobic 200 showed a much slower dissolution rate of
Fig. 7. Stability of the crystalline form of spray-dried TBM particles stored at 0% or 75% RH and 60 jC. (A) 0 days; (B) 1 day; (C) 7 days; (D) 14 days; (E) 21 days; (F) 28 days. (A) 0% RH, (B) 75% RH.
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Fig. 8. Stability of the crystalline form of TBM in solid dispersion particles with Aerosil 200 stored at 75% RH and 60 jC. (A) 0 days; (B) 1 day; (C) 7 days; (D) 14 days; (E) 21 days; (F) 28 days. (A) SD method; (B) Eva method.
TBM, although the crystalline form of TBM was metastable in these solid dispersion particles (Fig. 6). 3.4. Stability of TBM crystals in solid dispersion particles with hydrophilic silica Table 4 summarizes the transformation of crystalline forms of spray-dried TBM and TBM in SD or Eva solid dispersion particles in a matrix with Aerosil 200 or Sylysia 350 under the storage conditions of 0% or 75% RH at 60 jC. The powder X-ray diffraction patterns of each powder are shown in Figs. 7, 8 and 9. Under the storage conditions of 0% RH, the meta-stable crystalline form of spray-dried TBM was gradually converted into the stable form (Form I) within 28 days. However, in each type of SD solid dispersion particles, the initial meta-stable form of TBM was
maintained for 28 days. The stability of the meta-stable form of TBM in Eva solid dispersion particles depended on the type of carrier particle, as shown in Table 4. Under the condition of 75% RH, spray-dried TBM (Form II) was immediately converted into the stable form (Form I) within only 1 day. However, the meta-stable form of TBM crystals in SD solid dispersion particles was maintained for at least 7 days. In comparing their stability with respect to the type of carrier particles formulated in the solid dispersion, porous Sylysia 350 was more effective than nonporous Aerosil 200. The same tendency was observed for the Eva solid dispersion. As shown in Table 4, the meta-stable Form II in Eva solid dispersion with Sylysia 350 was unchanged up to 14 days, while the meta-stable Form III in that with Aerosil 200 was converted to the stable Form I within the same storage period.
Fig. 9. Stability of the crystalline form of TBM in solid dispersion particles with Sylysia 350 stored at 75% RH and 60 jC. (A) 0 days; (B) 1 day; (C) 7 days; (D) 14 days; (E) 21 days; (F) 28 days. (A) SD method, (B) Eva method.
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4. Discussion It was demonstrated that several polymorphs of TBM were formed in the solid dispersion with colloidal silica prepared by spray-drying or the usual evaporation method. There may be two main factors affecting the final crystalline form of the drug in this process: the rate of removal of solvent from the drug solution and the type of carrier formulated with the solid dispersion. The rapid solvent evaporation from the drug solution in the spraydrying method facilitated formation of the meta-stable Form II of TBM in the resultant particles irrespective of the type of silica. Because the meta-stable crystalline form was also produced by spray-drying the drug solution without silica particles, it was concluded that this form was due solely to the rapid removal of solvent from the solution. Formation of this crystalline form was also observed for Eva solid dispersion with porous silica (Sylysia 350 or Sylophobic 200), although the solvent evaporation speed was not rapid. In this case, formation of the meta-stable crystalline form may have been due to restriction of the crystallization of drug molecules in the pores of carrier particles during evaporation. Eva solid dispersion with nonporous silica of Aerosil 200 and Aerosil R972 resulted in different crystalline forms, i.e., Forms III and IV, respectively. These results suggest that a factor other than the porous structure must be introduced to account for the formation of polymorphs in the solid dispersion particles. This factor may be an interaction between the drug molecule and the surface of the carrier. The silanol group probably plays an important role in this drug-carrier interaction. It was supported by the fact that the different crystalline form was formed in the Eva solid dispersion by formulating Aerosil R972, in which silanol group was substituted by a hydrophobic moiety, in stead of Aerosil 200 having many silanol groups. In our previous study, we obtained the amorphous form of TBM by spray-drying a diluted ammonia solution of drug with Aerosil 200. It was supposed that the interaction between the silanol group and drug molecule in that system was stronger than that in the present organic solvent system. The dissolution property of TBM was dramatically improved with the solid dispersion system, as shown in Fig. 5. Both the meta-stable crystalline form of the drug and the increased hydrophilicity of the solid dispersion particle may have contributed to this improvement. The latter effect was confirmed by measuring the drug dissolution of solid dispersions with the hydrophobic silica (Fig. 6). The SD solid dispersion with the hydrophobic silica containing the crystalline Form II showed an extremely decreased dissolution rate. Eva solid dispersion with Sylophobic 200 containing the same crystalline Form II showed a little bit higher dissolution rate compared with the corresponding SD solid dispersion. It is presumed that the SD and Eva solid dispersions have different drug distributions in the solid
dispersion particles because of their different solvent evaporation speeds. It was interesting that the Eva solid dispersion with Aerosil R972 showed a much higher dissolution than the SD solid dispersion with the same silica. A possible explanation is that the crystalline Form IV, which was produced by the former method, had the improved dissolution property. Because it was thought that the crystalline form was produced by the drug interaction with the hydrophobic moiety of the silica, the resultant crystal surface might be relatively hydrophilic. More extensive studies may be needed to confirm the properties of the new crystalline Form IV. It was confirmed that the stability of the meta-stable crystalline form of the drug was much improved in the presence of the carrier particle, colloidal silica. The silica particles have high affinity with water molecules. This property may be partly responsible for the improved stability of the drug crystals. The peaks of TBM crystals in solid dispersion particles with Sylysia 350 on powder X-ray diffraction disappeared to reveal a halo pattern 14 days after starting (Fig. 9). This may have been due to the water molecules adsorbed on the surface of solid dispersion particles being condensed in their pores to help to form the amorphous state in the particles.
5. Conclusions Solid dispersion particles of TBM were successfully prepared by spray-drying an ethanol solution of drug containing silica fine particles. The resultant particles improved the dissolution of the incorporated drug. It was found that the drug incorporated in the solid dispersion particles by means of the spray-drying technique was in the meta-stable crystalline Form II. The meta-stable crystalline form of TBM was prepared by spray-drying the ethanol solution of drug without formulating the carrier particles. However, both the drug dissolution property and stability of the crystalline form were much improved by formulating the drug as solid dispersion particles.
Acknowledgements We thank Fuji Silysia for their provision of data on porous silica particles.
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Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method Hirofumi Takeuchi, Shinsuke Nagira, Hiromitsu Yamamoto, Yoshiaki Kawashima * Department of Pharmaceutical Engineering, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan Available online 27 April 2004
Abstract Solid dispersion particles of tolbutamide (TBM) were prepared by formulating nonporous (Aerosil 200 (hydrophilic), Aerosil R972 (hydrophobic)) or porous (Sylysia 350 (hydrophilic), Sylophobic 200 (hydrophobic)) silica as a carrier and applying the spray-drying (SD) or evaporation (Eva) method. In the solid dispersion particles prepared by the SD method, TBM existed in a meta-stable form (Form II) irrespective of the type of silica. On the other hand, when the Eva method was used, various crystalline forms of TBM were observed in the solid dispersion particles according to the type of silica. Polymorphs of Forms III and IV were prepared with Aerosil 200 and Aerosil R972, respectively, while crystalline Form II was obtained when either of the forms of porous silica, Sylysia 350 or Sylophobic 200, was formulated. The dissolution property of TBM in the solid dispersion particles prepared with hydrophilic silica was remarkably improved compared with those of the original TBM crystals (Form I) or spray-dried TBM without silica (Form II). In the case of hydrophobic silica, the release rate of TBM from the solid dispersion particles was much slower than that of original TBM. The meta-stable form of TBM in the solid dispersion particles was stable for at least 4 weeks when stored at 60 jC and 0% RH, while the spray-dried TBM without silica (Form II) was gradually converted to the stable form (Form I) under the same storage conditions. Under the humid storage conditions (60 jC, 75% RH), the spray-dried TBM without silica (Form II) immediately converted into the stable form (Form I) within 1 day, while TBM (Form II) in the solid dispersions in a matrix of silica was stable for at least 1 week. D 2004 Elsevier B.V. All rights reserved. Keywords: Tolbutamide; Polymorphs; Solid dispersion particle; Porous silica; Spray-drying
1. Introduction Improvement of the dissolution property of pharmaceuticals is extremely important, especially since the percentage of drugs with poor water solubility has increased in recent years. Various methods have been reported to improve the dissolution property of drugs, such as grinding, formation of inclusion compound with cyclodextrin, and solid dispersion with water soluble polymers. According to the Noyes – Whitney equation [1], the dissolution rate of a drug depends on its surface area and solubility. It is easier to increase the surface area by reducing the particle size of drug crystals than to increase the drug solubility. The particle size may be easily reduced by simple grinding. However, the ground crystals tend to agglomerate, thereby creating a surface with higher energy than that of the original crystals, and reducing the effective surface area for dissolution. * Corresponding author. Tel.: +81-58-237-3931; fax: +81-58-237-6524. E-mail address: [email protected] (Y. Kawashima). 0032-5910/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2004.03.007
Solid dispersion is a useful method to disperse drugs in the molecular state in a carrier matrix [2,3]. The interaction between the drug molecule and carrier is responsible for drug dispersion, and may depress the crystallization of drug in the prepared system. The most popular carrier materials are water soluble polymers such as PEG [4] or PVP [5]. However, it is often complained that drugs prepared by solid dispersion with a water-soluble polymer carrier tend to be sticky or tacky. This property leads to a decrease in the recovery of solid dispersion in preparation and also to difficulty of handling in the subsequent processes. Milling or mixing with other excipients is required before preparing the final dosage forms by plugging into capsules or tabletting. These processes sometimes facilitate crystallization of the drug in an amorphous state in the solid dispersion. The change in the crystalline forms of drug in the dosage form affects its bioavailability after administration. The spray-drying technique is a useful method to obtain spherical particles which have small size and narrow distribution. This method also has the advantage that granulation
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and drying are completed in one step. In a previous paper [6], we demonstrated that solid dispersion particles of a poorly water soluble drug, tolbutamide (TBM), could be prepared by spray-drying the drug solution with a nonporous silica, Aerosil 200. It was also confirmed that the drug was molecularly dispersed in the matrix formed with silica particles. The resultant solid dispersion particles were freely flowing and remarkably improved the dissolution property of the drug. Silicas having many silanol groups on their surfaces may be able to form hydrogen bonds with drug molecules [7]. There are two types of silica, porous and nonporous. Several grades of silica particle having different properties, such as particle size, degree of hydrophilicity, and pore structure, are available for both types. In the pharmaceutical field, other porous materials, such as calcium silicate [8,9], controlled pore glass [10,11], and porous cellulose [12], are also used to formulate solid dosage forms. It has been pointed out that the porous structure itself confers special characteristics, such as a decrease of melting point and a decrease in the crystallinity of drugs entrapped in the pores [10 – 13]. Thus, a porous silica is expected to be successfully applied to the solid dispersion formulation as its carrier material. TBM, which is used in this study as a model drug, is a poorly water soluble drug for diabetics. Four types of polymorph (types I, II, III, and IV) have been reported for TBM [14], and the dissolution, bioavailability, and stability of these polymorphs have been investigated by Kimura et al. [15,16]. In the present study, we investigated the solid dispersion particles prepared by spray-drying an ethanol solution of TBM with several colloidal silica having different physicochemical properties, e.g., different particle structures and hydrophilicities. The effect of the properties of the carrier particles on the polymorphs and dissolution property of drug in solid dispersions was examined. The stability of the metastable crystalline form of the drug in storage was also tested.
Table 2 Particle size of solid dispersion particles prepared by the SD method Sample
Particle size (Am) D16
D50
D84
Original TBM Spray-dried TBM SD solid dispersion with Aerosil 200 SD solid dispersion with Sylysia 350 SD solid dispersion with Aerosil R972 SD solid dispersion with Sylophobic 200
15.4 F 0.6 6.4 F 0.3 2.4 F 0.3
28.7 F 0.5 11.6 F 0.6 5.6 F 0.1
48.9 F 1.6 18.4 F 1.6 8.8 F 1.6
1.7 F 0.0
3.2 F 0.0
5.2 F 0.0
1.7 F 0.1
3.7 F 0.1
6.4 F 0.2
1.7 F 0.1
3.1 F 0.1
5.0 F 0.3
The data are the average values of four runs.
Aerosil, Japan; Sylysia 350 and Sylophobic 200 from Fuji Silysia, Japan) were used as obtained. Aerosil 200 and Aerosil R972 are nonporous forms of silica, and Sylysia 350 and Sylophobic 200 are porous forms. Aerosil 200 and Sylysia 350 are hydrophilic and Aerosil R972 and Sylophobic 200 are hydrophobic. Sylophobic 200 was prepared by introducing a hydrophobic moiety into Sylysia 350 in the preparation process. The properties of the silicas used are shown in Table 1. The data were obtained from the catalogs of the suppliers. We also measured the particle size of Sylysia 350 and Sylophobic 200 using a laser diffraction size analyzer (LDSA-2400A; Tonichi-Computer, Japan) in combination with a powder dispersion instrument (PD-10S; Tonichi-Computer). The specific surface area of silica was also measured by the N2 adsorption method (Gemini; Shimadzu) after degassing the sample powder at 40 jC overnight (Flow Prep060; Shimadzu). The values shown in parenthesis in Table 1 confirmed the validity of the values in the catalogs. All other chemicals and solvents were of reagent grade. 2.2. Preparation of solid dispersion particles
2. Experimental 2.1. Materials TBM was a gift from Aventis Pharma, Japan. Several types of silica (Aerosil 200 and Aerosil R972 from Nihon
Solid dispersion particles of TBM with fine silica particles were prepared using two different methods of solvent removal: the spray-drying (SD) method and the evaporation (Eva) method. For the preparation of solid dispersion particles by the SD method, 1.0 g of silica was suspended in 50.0 ml of ethanol solution into which 1.0 g of TBM had
Table 1 Physicochemical properties of Aerosil 200, Aerosil R972, Sylysia 350 and Sylophobic 200 Sample
Porous or nonporous
Hydrophilic or hydrophobic
Particle size (Am)
Specific surface area (m2/g)
Pore size (nm)
Pore volume (ml/g)
Aerosil 200 Aerosil R972 Sylysia 350 Sylophobic 200
Nonporous
Hydrophilic Hydrophobic Hydrophilic Hydrophobic
0.012 0.016 3.9 (3.3 F 0.1) 3.9 (3.0 F 0.1)
200 (193.2 F 0.9) 110 300 (251.3 F 1.5) N.D.
21.0 N.D.
1.60 N.D.
Porous
N.D.: not determined. The values were obtained from the catalog of Aerosil (Nihon aerosil) or Sylysia. (Fuji silysia). The values measured in the present study are given in parenthesis.
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Fig. 1. Observation of solid dispersion particles of tolbutamide with Aerosil 200 or Sylysia 350 prepared by the SD or Eva method. (A) Aerosil 200;(B) Sylysia 350; (C) SD solid dispersion with Aerosil 200; (D) SD solid dispersion with Sylysia 350.
been dissolved. This suspension was fed to a spray dryer (GS31; Yamato, Japan) at rate of 10 ml/min and sprayed into the chamber from a nozzle with a diameter of 406 Am at a pressure of 0.12 to 0.15 MPa. The inlet and outlet temperatures of the drying chamber were maintained at 100 and 70 jC, respectively. The spray-dried TBM particles
were prepared from the ethanol solution of TBM under the same conditions. In the preparation by the Eva method, 0.5 g of silica was suspended in 25.0 ml of ethanol solution into which 0.5 g of TBM had been dissolved. This suspension was evaporated in an evaporator (N-2NW; EYELA, Japan) with a rotation speed of 4 rpm at 60 jC for 25 min. The
Fig. 2. Powder X-ray diffraction patterns of original TBM crystals, spray-dried TBM crystals, and evaporated TBM crystals. (A) Original TBM crystals; (B) spray-dried TBM; (C) evaporated TBM.
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Table 3 Crystalline form of original TBM crystals, spray-dried TBM, evaporated TBM and TBM in solid dispersion particles Preparation method
Silica
Crystalline form
SD
– Sylysia 350 Aerosil 200 Sylophobic 200 Aerosil R972 – Sylysia 350 Aerosil 200 Sylophobic 200 Aerosil R972
II II II II II I II III II IV
Eva
resultant solid dispersion in a flask was softly ground by a mortar and pestle. All solid dispersion particles were dried in a desiccator with blue silica gel under reduced pressure for 1 day before testing their physicochemical properties.
medium (pH 6.8) for a disintegration test with paddle stirring at a rotation speed of 100 rpm at 37 jC, as specified in JPXIV. The drug concentration in the medium was measured spectrophotometrically at 226 nm (UV-160A; Shimadzu, Japan). 2.5. Stability test Sample particles were stored in desiccators with 0% RH (P2O5 powder) or 75% RH (Saturated solution with NaCl) at 60 jC. The crystalline form of TBM in solid dispersion particles was measured by the powder X-ray diffraction method (RAD-IC; Rigaku) at appropriate time intervals.
3. Results 3.1. Physicochemical properties of solid dispersion particles
2.3. Physicochemical property of solid dispersion particles The size of solid dispersion particles was measured by a laser diffraction size analyzer (LDSA-2400A; Tonichi-Computer, Japan). The particle shape was observed by scanning electron microscopy (JSM-T330A; Nihon Denshi, Japan). The crystalline form of TBM in solid dispersion particles was measured by the powder X-ray diffraction method (RAD-IC; Rigaku Denki, Japan). 2.4. Dissolution test The dissolution test was carried out according to Japanese Pharmacopoeia XIV. Sample (25 mg of TBM or 50 mg of solid dispersion particles) was added to 900 ml of No. 2
Table 2 lists the particle size of spray-dried TBM and TBM solid dispersion particles prepared by the spray-drying method (SD solid dispersion). The particle size of spraydried TBM and TBM solid dispersion particles was smaller than that of original TBM crystals. The type of silica did not affect the size of the resulting solid dispersion particles. It was characterized that the particle size was comparable to that of original Sylysia 350 or Sylophobic 200 particles. This fact suggested that the drug molecules or crystals were well dispersed on the surface of the porous silica particles to form the solid dispersion particles. On the other hand, the particle size of SD solid dispersion particles prepared with nonporous silica was much larger than that of the silica particles shown in Table 1. It means that the SD solid
Fig. 3. Powder X-ray diffraction patterns of TBM in solid dispersion particles with Aerosil 200 or Sylysia 350 prepared by the SD or Eva method. (A) SD solid dispersion with Aerosil 200; (B) SD solid dispersion with Sylysia 350; (C) Eva solid dispersion with Aerosil 200; (D) Eva solid dispersion with Sylysia 350.
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Fig. 4. Powder X-ray diffraction patterns of TBM in solid dispersion particles with Aerosil R972 or Sylophobic 200 prepared by the SD or Eva method. (A) SD solid dispersion with Aerosil R972; (B) SD solid dispersion with Sylophobic 200; (C) Eva solid dispersion with Aerosil R972; (D) Eva solid dispersion with Sylophobic 200.
dispersion particles are the agglomerates of the nonporous silica particles. The size of solid dispersion particles prepared by the evaporation method (Eva solid dispersion) may depend on the grinding conditions. The mass of solid dispersion particles prepared with Aerosil 200 was so hard that it could not be ground into fine particles under soft grinding conditions (D50: 22.5 F 0.92 Am). On the other hand, the mass of solid dispersion particles prepared with Sylysia 350 was
soft and easily ground. The average particle size (D50) of the resulting solid dispersion particles was 4.29 F 0.16 Am, which was almost comparable to that of the original Sylysia 350 particles or the solid dispersion particles prepared by spray-drying. This result suggested that the same solid dispersion particles with Sylysia 350 could be prepared using either preparation method. The SEM photographs of these particles are shown in Fig. 1. It was confirmed that Aerosil 200 particles formed
Fig. 5. Dissolution profile of TBM from solid dispersion particles with Aerosil 200 or Sylysia 350 prepared by the SD or Eva method. : Original TBM crystals; .: Spray dried TBM; E: SD solid dispersion with Aerosil 200; n: SD solid dispersion with Sylysia 350; D: Eva solid dispersion with Aerosil 200; 5: Eva solid dispersion with Sylysia 350.
Fig. 6. Dissolution profile of TBM from solid dispersion particles with Aerosil R972 or Sylophobic 200 prepared by the SD or Eva method. : Original TBM crystals; E: SD solid dispersion with Aerosil R972; n: SD solid dispersion with Sylophobic 200; D: Eva solid dispersion with Aerosil R972; 5: Eva solid dispersion with Sylophobic 200.
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Table 4 Stability of the crystalline form of TBM in solid dispersion particles stored at 0% or 75% RH and 60 jC Preparation method
SD
SD
Silica
–
Aerosil 200
Sylysia 350
Aerosil 200
Sylysia 350
Initial (days)
II
II
II
III
II
1 7 14 21 28 1 7 14 21
I + II I + II I + II I + II I I I I I
II II II II II II II I + II I + II
III III I + III I + II I + III III I + III I I
28
I
I + II
II II II II II II II II Hallo pattern Hallo pattern
II II II II II II II II Halo pattern Hallo pattern
0% RH 60 jC
75% RH 60 jC
Eva
I
agglomerates and the SD solid dispersion particles with Aerosil 200 were smaller than the agglomerates of Aerosil 200. As confirmed by particle size measurement, there was little difference between the Sylysia 350 particles and SD solid dispersion particles sprayed with Sylysia 350. 3.2. Crystalline form of TBM in solid dispersion particles Powder X-ray diffraction patterns of original TBM crystals and TBM particles prepared by spray-drying or evaporating the ethanol solution of TBM are shown in Fig. 2. The crystalline form of spray-dried TBM was meta-stable (Form II), while evaporated TBM took the same crystalline form as the original TBM crystals, i.e., the stable form (Form I). This result suggested that the evaporation rate of
solvent affected the resultant crystalline form. The rapid evaporation rate in spray-drying may facilitate the formation of the meta-stable form. Table 3 summarizes the crystalline forms of TBM in SD or Eva solid dispersion particles prepared with various types of silica. In the case of solid dispersion particles prepared by the SD method, the crystalline form of TBM in solid dispersion particles was meta-stable (Form II), which was also the form of the spray-dried TBM without silica. However, in the Eva method, various crystalline forms of TBM, including Type III and IV, were detected depending on the type of the silica particles formulated. When Sylysia 350 or Sylophobic 200 particles were formulated, the metastable form (Form II) of TBM was obtained. Because these silica particles have similar pore structures, the pores seemed to be responsible for formation of the meta-stable crystalline Form II under the evaporation conditions. The powder X-ray diffraction patterns of the typical samples are shown in Figs. 3 and 4. 3.3. Dissolution property of TBM in solid dispersion particles The dissolution profiles of TBM from the various solid dispersion particles were measured (Figs. 5 and 6). All solid dispersion particles with hydrophilic silica remarkably improved the dissolution rate of TBM compared with original TBM crystals (Fig. 5). The meta-stable TBM particles prepared by spray-drying the drug solution without formulating the silica particles (Form II) also improved the dissolution property, but the dissolution was still lower than that by solid dispersion. This result implied that the hydrophilic property of the silica particles contributed to the improved drug dissolution from the solid dispersion. The solid dispersion particles sprayed with Aerosil R972 or Sylophobic 200 showed a much slower dissolution rate of
Fig. 7. Stability of the crystalline form of spray-dried TBM particles stored at 0% or 75% RH and 60 jC. (A) 0 days; (B) 1 day; (C) 7 days; (D) 14 days; (E) 21 days; (F) 28 days. (A) 0% RH, (B) 75% RH.
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Fig. 8. Stability of the crystalline form of TBM in solid dispersion particles with Aerosil 200 stored at 75% RH and 60 jC. (A) 0 days; (B) 1 day; (C) 7 days; (D) 14 days; (E) 21 days; (F) 28 days. (A) SD method; (B) Eva method.
TBM, although the crystalline form of TBM was metastable in these solid dispersion particles (Fig. 6). 3.4. Stability of TBM crystals in solid dispersion particles with hydrophilic silica Table 4 summarizes the transformation of crystalline forms of spray-dried TBM and TBM in SD or Eva solid dispersion particles in a matrix with Aerosil 200 or Sylysia 350 under the storage conditions of 0% or 75% RH at 60 jC. The powder X-ray diffraction patterns of each powder are shown in Figs. 7, 8 and 9. Under the storage conditions of 0% RH, the meta-stable crystalline form of spray-dried TBM was gradually converted into the stable form (Form I) within 28 days. However, in each type of SD solid dispersion particles, the initial meta-stable form of TBM was
maintained for 28 days. The stability of the meta-stable form of TBM in Eva solid dispersion particles depended on the type of carrier particle, as shown in Table 4. Under the condition of 75% RH, spray-dried TBM (Form II) was immediately converted into the stable form (Form I) within only 1 day. However, the meta-stable form of TBM crystals in SD solid dispersion particles was maintained for at least 7 days. In comparing their stability with respect to the type of carrier particles formulated in the solid dispersion, porous Sylysia 350 was more effective than nonporous Aerosil 200. The same tendency was observed for the Eva solid dispersion. As shown in Table 4, the meta-stable Form II in Eva solid dispersion with Sylysia 350 was unchanged up to 14 days, while the meta-stable Form III in that with Aerosil 200 was converted to the stable Form I within the same storage period.
Fig. 9. Stability of the crystalline form of TBM in solid dispersion particles with Sylysia 350 stored at 75% RH and 60 jC. (A) 0 days; (B) 1 day; (C) 7 days; (D) 14 days; (E) 21 days; (F) 28 days. (A) SD method, (B) Eva method.
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4. Discussion It was demonstrated that several polymorphs of TBM were formed in the solid dispersion with colloidal silica prepared by spray-drying or the usual evaporation method. There may be two main factors affecting the final crystalline form of the drug in this process: the rate of removal of solvent from the drug solution and the type of carrier formulated with the solid dispersion. The rapid solvent evaporation from the drug solution in the spraydrying method facilitated formation of the meta-stable Form II of TBM in the resultant particles irrespective of the type of silica. Because the meta-stable crystalline form was also produced by spray-drying the drug solution without silica particles, it was concluded that this form was due solely to the rapid removal of solvent from the solution. Formation of this crystalline form was also observed for Eva solid dispersion with porous silica (Sylysia 350 or Sylophobic 200), although the solvent evaporation speed was not rapid. In this case, formation of the meta-stable crystalline form may have been due to restriction of the crystallization of drug molecules in the pores of carrier particles during evaporation. Eva solid dispersion with nonporous silica of Aerosil 200 and Aerosil R972 resulted in different crystalline forms, i.e., Forms III and IV, respectively. These results suggest that a factor other than the porous structure must be introduced to account for the formation of polymorphs in the solid dispersion particles. This factor may be an interaction between the drug molecule and the surface of the carrier. The silanol group probably plays an important role in this drug-carrier interaction. It was supported by the fact that the different crystalline form was formed in the Eva solid dispersion by formulating Aerosil R972, in which silanol group was substituted by a hydrophobic moiety, in stead of Aerosil 200 having many silanol groups. In our previous study, we obtained the amorphous form of TBM by spray-drying a diluted ammonia solution of drug with Aerosil 200. It was supposed that the interaction between the silanol group and drug molecule in that system was stronger than that in the present organic solvent system. The dissolution property of TBM was dramatically improved with the solid dispersion system, as shown in Fig. 5. Both the meta-stable crystalline form of the drug and the increased hydrophilicity of the solid dispersion particle may have contributed to this improvement. The latter effect was confirmed by measuring the drug dissolution of solid dispersions with the hydrophobic silica (Fig. 6). The SD solid dispersion with the hydrophobic silica containing the crystalline Form II showed an extremely decreased dissolution rate. Eva solid dispersion with Sylophobic 200 containing the same crystalline Form II showed a little bit higher dissolution rate compared with the corresponding SD solid dispersion. It is presumed that the SD and Eva solid dispersions have different drug distributions in the solid
dispersion particles because of their different solvent evaporation speeds. It was interesting that the Eva solid dispersion with Aerosil R972 showed a much higher dissolution than the SD solid dispersion with the same silica. A possible explanation is that the crystalline Form IV, which was produced by the former method, had the improved dissolution property. Because it was thought that the crystalline form was produced by the drug interaction with the hydrophobic moiety of the silica, the resultant crystal surface might be relatively hydrophilic. More extensive studies may be needed to confirm the properties of the new crystalline Form IV. It was confirmed that the stability of the meta-stable crystalline form of the drug was much improved in the presence of the carrier particle, colloidal silica. The silica particles have high affinity with water molecules. This property may be partly responsible for the improved stability of the drug crystals. The peaks of TBM crystals in solid dispersion particles with Sylysia 350 on powder X-ray diffraction disappeared to reveal a halo pattern 14 days after starting (Fig. 9). This may have been due to the water molecules adsorbed on the surface of solid dispersion particles being condensed in their pores to help to form the amorphous state in the particles.
5. Conclusions Solid dispersion particles of TBM were successfully prepared by spray-drying an ethanol solution of drug containing silica fine particles. The resultant particles improved the dissolution of the incorporated drug. It was found that the drug incorporated in the solid dispersion particles by means of the spray-drying technique was in the meta-stable crystalline Form II. The meta-stable crystalline form of TBM was prepared by spray-drying the ethanol solution of drug without formulating the carrier particles. However, both the drug dissolution property and stability of the crystalline form were much improved by formulating the drug as solid dispersion particles.
Acknowledgements We thank Fuji Silysia for their provision of data on porous silica particles.
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