Vo 2013

EJPB 11503 No.
of Pages 15, Model 5G

23 September 2013
European Journal of Pharmaceutics and Biopharmaceutics xxx (2013) xxx–xxx

1
Contents lists available at ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics

journal homepage: www.elsevier.com/locate/ejpb
2 Review article
6
4 Current trends and future perspectives of solid dispersions containing
7
5 poorly water-soluble drugs
8 Q1 Chau Le-Ngoc Vo, Chulhun Park, Beom-Jin Lee ⇑
9 Q2 Bioavailability Control Laboratory, College of Pharmacy, Ajou University, Suwon, Republic of Korea
10
11
a r t i c l e i n f o a b s t r a c t
1
2 3
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14 Article history: Over 40% of active pharmaceutical ingredients (API) under development pipelines are poorly water- 28
15 Received 8 April 2013 soluble drugs which limit formulation approaches, clinical application and marketability because of their 29
16 Accepted in revised form 9 September 2013 low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements 30
17 Available online xxxx
in overcoming these issues with several successfully marketed products. A number of key references that 31
describe state-of-the-art technologies have been collected in this review, which addresses various 32
18 Keywords: pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs 33
19 Classification of solid dispersions
according to the four generations of solid dispersions. This article reviews critical aspects and recent 34
20 Four generation-to-generation development
21 Poorly water-soluble drug
advances in formulation, preparation and characterization of solid dispersions as well as in-depth 35
22 Problems and issues pharmaceutical solutions to overcome some problems and issues that limit the development and market- 36
23 Mechanism of drug release ability of solid dispersion products. 37
24 Preparation and characterization Ó 2013 Published by Elsevier B.V. 38
25 Future perspectives and strategies
26
39
40
41 1. Introduction development such as salt formation [7], prodrug formation [8], 63

particle size reduction [9], complexation [10], micelles [11], micro- 64
42 The poor aqueous solubility and dissolution rate of API is one of emulsions [12], nanoemulsions [13], nanosuspensions [14], solid– 65
43 the biggest challenges in pharmaceutical development and is lipid nanoparticle [15] and solid dispersion which is considered 66
44 becoming more common among new drug candidates over the one of the most successful strategies to improve the dissolution 67
45 past two decades due to the use of high throughput and combina- profile of poorly soluble drugs. The term solid dispersions has been 68
46 torial screening tools during the drug discovery and selection defined as a dispersion of one or more API in an inert carrier or 69
47 phase [1–3]. According to the Biopharmaceutics Classification matrix at the solid state prepared by solvent, melting or solvent– 70
48 System (BCS), a drug compound is poorly soluble if the highest melting method [16]. The API in solid dispersions can be dispersed 71
49 dose strength is not soluble in 250 ml aqueous media over the in separate molecules, amorphous particles, or crystalline particles 72
50 pH ranges at 37 °C [4]. These compounds mostly belong to Class while the carrier can be in crystalline or amorphous state. Numer- 73
51 II (IIa or IIb), which are poorly soluble and highly permeable ous studies on solid dispersions have been published and have 74
52 according to the pH of the gastrointestinal fluid and tend to present showed many advantageous properties of solid dispersions in 75
53 dissolution-limited absorption [5]. Despite their high permeability, improving the solubility and dissolution rate of poorly water- 76
54 these drugs often have low oral bioavailability because of their soluble drugs. These advantages include reducing particle size, 77
55 slow and limited release of drug in gastrointestinal fluid [6]. There- possibly to molecular level, enhancing wettability and porosity, 78
56 fore, one of the major challenges of the pharmaceutical industry is as well as changing drug crystalline state, preferably into 79
57 to apply strategies that improve the dissolution and/or apparent amorphous state [6]. 80
58 solubility of poorly soluble drugs to develop such problematic Despite such high active research interests, the number of mar- 81
59 compounds into orally bioavailable and therapeutic effective drugs keted products arising from solid dispersion approaches is disap- 82
60 [3,5]. pointingly low. This low number is mainly due to scale-up 83
61 Various approaches to overcome the poor aqueous solubility of problems and physicochemical instability in the manufacturing 84
62 drug candidates have been investigated in drug research and process or during storage leading to phase separation and 85
crystallization [17–20]. Only a few commercial products have been 86
marketed during the past half-century (Table 1). Therefore, 87
⇑ Corresponding author. Bioavailability Control Laboratory, College of Pharmacy,
Ajou University, Suwon 443-749, Republic of Korea. Tel.: +82 31 219 3442;
in-depth knowledge that has been acquired on various aspects of 88
fax: +82 31 212 3653. solid dispersions such as carrier properties, preparation methods, 89
E-mail address: beomjinlee@gmail.com (B.-J. Lee). physicochemical characterization techniques as well as the 90
0939-6411/$ - see front matter Ó 2013 Published by Elsevier B.V.

http://dx.doi.org/10.1016/j.ejpb.2013.09.007
Please cite this article in press as: C.-L.N. Vo et al., Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs, Eur. J.
Pharm. Biopharm. (2013), http://dx.doi.org/10.1016/j.ejpb.2013.09.007
EJPB 11503 No. of Pages 15, Model 5G
23 September 2013
2 C.Le-Ngoc Vo et al. / European Journal of Pharmaceutics and Biopharmaceutics xxx (2013) xxx–xxx
Table 1 carrier to form eutectic mixture with sulphathiazole. In crystalline 112

Marketed products using solid dispersions [5,72,118]. solid dispersions, a crystalline drug is dispersed within a crystal- 113
Product Model drug Carrier type Dosage form line carrier forming a eutectic or monotectic mixture [16,21]. In 114
Certican Ò
Everolimus HPMC Tablet the eutectic mixture, the melting point of the mixture is lower than 115
CesametÒ Nabilone PVP Tablet the melting point of the drug and carrier whereas in the monotec- 116
Gris-PEGÒ Griseofulvin PEG Tablet tic mixture, the melting point of the carrier and drug are constant. 117
IsoptinÒ SR-E Verapamil HPC/HPMC Tablet The eutectic mixture is always more preferable because both the 118
NivadilÒ Nivaldipine HPMC Tablet
RezulinÒ Troglitazone HPMC Tablet
drug and carrier will crystallize simultaneously in cooling process, 119
KaletraÒ Lopinavir, Ritonavir PVPVA Tablet resulting in a well-dispersed state of the drug in carrier, thus 120
IntelenceÒ Etravirine HPMC Tablet enhancing the dissolution rate. Moreover, the process temperature 121
ZelborafÒ Vemurafenib HPMCAS Tablet for melting eutectic mixture is lower than that of monotectic mix- 122
IncivekÒ Telaprevir HPMCAS-M Tablet
ture. However, if the mixture of the drug and carrier is not exactly 123
CrestorÒ Rosuvastatin HPMC Tablet
AfeditabÒ CR Nifedipin Poloxamer/PVP Tablet at the eutectic composition, the solid dispersion will contain a 124
FenoglideÒ Fenofibrate PEG Tablet mixture of the microfine dispersion and another component as a 125
PrografÒ Tacrolimus HPMC Capsule separate phase because one component will progressively crystal- 126
SporanoxÒ Itraconazole HPMC Capsule line until the eutectic composition is reached. In fact the number of 127
studied solid dispersions having the exact eutectic composition is 128
very limited [22]. The API in crystalline solid dispersions may also 129
91 pharmaceutical mechanism of matrix formation and drug release exist in amorphous particles or separate molecules (crystalline 130
92 are very important to ensure the preparation of a productive and solid solutions). In crystalline solid solutions, the drug molecules 131
93 marketable solid dispersion. The aim of this review is to provide can replace carrier molecule in the crystal lattice (substitutional 132
94 new knowledge from recent advances on solid dispersion areas crystalline solid solutions) or occupy the interstitial spaces 133
95 to overcome some problems and issues that limit the marketability between the solvent molecules in the crystal lattice (interstitial 134
96 of solid dispersion products. As a continued work of previous crystalline solid solutions) [23]. 135
97 reviews in this field, this article newly suggests the four classifica- Crystalline carriers in the first generation solid dispersions com- 136
98 tions of solid dispersions according to the development by genera- prise of urea [21] and sugars such as sorbitol and mannitol [24]. 137
99 tion-to-generation that has been investigated so far. Finally, the These carriers, especially sugars, have high melting point which 138
100 future perspectives and strategies of solid dispersions are also is not favorable for preparing solid dispersions by melting method. 139
101 discussed. Urea exhibits high solubility in water and many common organic 140
solvents while sugars have poor solubility in most of organic 141
102 2. The classification of solid dispersions solvents; therefore, sugars were less commonly used than other 142
carriers. The particle size reduction, wettability improvement and 143
103 Depending on the physical state of the carrier which is crystal- polymorphic change are the main reasons for enhancing drug 144
104 line or amorphous, the solid dispersions are divided into crystalline solubility and dissolution rate. Zajc et al. [25] prepared the solid 145
105 solid dispersions and amorphous solid dispersions respectively. dispersions of nifedipine and mannitol with different ratios by 146
106 The solid dispersions can also be classified into four generations melting method. The results showed markedly enhanced dissolu- 147
107 based on their composition (Fig. 1). tion rate of nifedipine in comparison with physical mixture 148
although the crystalline state of nifedipine did not change. The 149
108 2.1. First generation SEM results elucidated the mechanism of dissolution rate enhance- 150
ment which is improving the wettability of nifedipine crystals. 151
109 The first generation solid dispersions are crystalline solid dis- Okonogi et al. [26] also tried to improve the dissolution rate of 152
110 persions. Sekiguchi and Obi [21] prepared the first solid disper- ofloxacin by solid dispersion systems with urea and mannitol. 153
111 sions for pharmaceutical application in which urea was used as a The dissolution rate of ofloxacin was significantly increased in urea 154
Poorly water soluble drug
+CC +AP +SFP + WIP or SP
+WIP
+SF +WIP
1stgeneration 2nd generation 3rd generation 4th generation
+SF
- Low dissolution - Dissolution rate - Highest dissolution - Dissolution rate

rate due to crystalline - Precipitation under rate - Controlled release
carrier supersaturation - Precipitation
- Low stability - Low stability under
supersaturation
- Stability
Fig. 1. Composition and properties of four generations of solid dispersions. CC: crystalline carrier, AP: amorphous polymer, SFP: surfactant polymer, WIP: water insoluble
polymer, SP: swellable polymer, SF: surfactant, ("): increase, (;): decrease.
23 September 2013
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includes povidone (PVP) [33], polyethylene glycol (PEG) [34], 189

crospovidone (PVP-CL) [35], polyvinypyrrolidone-co-vinylacetate 190
(PVPVA) [34], and polymethacrylates [36]. The natural product 191
based polymer consists of cellulose derivatives such as hydroxy- 192
propylmethyl cellulose (HPMC) [37], hydroxypropylcellulose 193
(HPC) [38], hydroxypropylmethylcellulose phthalate (HPMCP) 194
[39], hydroxylpropylmethylcellulose acetate succinate (HPMCAS) 195
[40], starch (corn starch, potato starch) [41] and sugar glass (treha- 196
lose, sucrose, inulin) [42]. Among them, HPMC, PEG and PVP are 197
most widely used [41]. Unlike other amorphous polymers listed 198
above, PEG has semi-crystalline structure but very low melting 199
point (below 65 °C) regardless of its molecular weight. Therefore, 200
PEG is very suitable for the preparation of solid dispersions by 201
the melting method especially when the drug is heat sensitive. In 202
contrast, PVP has relatively high glass transition temperature so 203
it is hardly utilized for the melting method [23]. All of these poly- 204
mers are soluble in some organic solvents or even wide variety of 205
solvents in the cases of PEG, PVP, HPC; therefore, these polymers 206
can be applied to prepare solid dispersions by the solvent method. 207
Except crospovidone, all of these polymers have high solublility in 208
water and thus can improve the drug’s wettability when the solid 209
Fig. 2. Modeling and comparison of dissolution profiles of four generations of solid
dispersions in supersaturated conditions, (0) pure API, (1) the first generation solid dispersions are dispersed in water. Although crospovidone is not 210
dispersions which show improvement in dissolution rate compared to the pure API, soluble in water, this hydrophyllic polymer quickly swells when 211
(2) the second generation solid dispersions which have improved dissolution profile contact to water and enhances the drug release rate [35]. The aque- 212
compared to the first generation thanks to their faster dissolution rate, (3) the third ous solubility of these polymers often decreases and the viscosity 213
generation solid dispersions which have improved dissolution profile compared to
becomes higher when their chain lengths or molecular weights 214
second generation thanks to their faster dissolution rate and lower precipitation
rate and extend in supersaturated state, (4) the fourth generation solid dispersions increase. The high viscosity polymers can prevent the recrystalliza- 215
which have improved dissolution profile in a controlled or zero-order manner. tion of drugs in the preparation, storage and dissolution process. 216
However, they can hinder the dispersion of drugs in carriers in 217
the preparation process and delay the dissolution rate of drugs 218
155 and mannitol based solid dispersions. Urea based solid dispersions when the solid dispersions are dispersed in water. Therefore, the 219
156 showed higher solubility and dissolution rate than mannitol based molecular weight of polymers is very important factor to select a 220
157 solid dispersions because urea reduced the crystallinity of ofloxa- polymer as a carrier. In fact, PEG with molecular weights of 221
158 cin more than mannitol which was proved by PXRD and DSC re- 1500–20,000 and PVP with molecular weights of 2500–50,000 222
159 sults. The main disadvantage of crystalline solid dispersions is (K12 to K30) are commonly used in solid dispersions [23]. PEG 223
160 the high thermodynamic stability of the carriers that lowers their with a very low molecular weight can make the solid dispersions 224
161 dissolution rate compared to amorphous solid dispersions (Fig. 2). too soft and sticky to manufacture tablets or capsules whereas 225
PVP with very high molecular weight will reduce the drug release 226
162 2.2. Second generation rate because of its low solubility and high viscosity [43]. The inter- 227
action between the drug and carrier is also important for carrier 228
163 The second generation solid dispersions contain amorphous selection. Some drugs have plasticizing effect on polymer or form 229
164 carriers which are mostly polymers. Amorphous solid dispersions hydrogen bonds with carriers. These interactions can affect the 230
165 can be classified into amorphous solid solutions (glass solutions) preparation process, the drug dissolution rate, the physical proper- 231
166 and amorphous solid suspensions according to the physical state ties and the stability of the solid dispersions. Karavas et al. [44] 232
167 of the drug. In amorphous solid solution the drug and amorphous prepared felodipine solid dispersions by using different types of 233
168 carrier are completely miscible to form molecularly homogenous PVP and PEG as carriers. FTIR data showed hydrogen bonding be- 234
169 mixture while amorphous solid suspension consists of two sepa- tween felodipine and both polymers. In the felodipine–PVP disper- 235
170 rate phases. Amorphous solid suspensions are formed when the sions, the drug existed as amorphous nanoparticles whereas in 236
171 drug has limited carrier solubility or an extremely high melting felodipine–PEG dispersions, the drug was dispersed as crystalline 237
172 point [27]. In these systems, the small drug particles mainly in microparticles. This was explained by the higher hydrogen bonding 238
173 amorphous state are dispersed in amorphous carriers. It is impor- in the FELO–PVP complex compared to FELO–PEG complex. In that 239
174 tant to note that the API often exists more than one state in solid research, the physical state (amorphous or crystalline) and the par- 240
175 dispersions, for instance, an API can both dissolve and suspend in ticle size of felodipine in the solid dispersions were determined by 241
176 a carrier or exist in amorphous and crystalline state at the same the interaction between drug and polymer. Kohri et al. [32] investi- Q3 242
177 time. In amorphous solid dispersions, the API is dispersed in very gated the oral bioavailability of albendazole solid dispersion gran- 243
178 small size (molecular, amorphous particle or small crystals) and ule using HPMC, HPMCP and the mixtures thereof as carriers. The 244
179 exists in supersaturated state in amorphous carriers because of results showed that all formulations significantly improved the 245
180 forced solubilization [28–30]. The amorphous carriers can also dissolution profile of albendazole and the solid dispersions con- 246
181 increase the wettability and dispersibility of drugs as well as inhi- taining both HPMC and HPMCP as carriers not only had excellent 247
182 bit the precipitation process of drugs when amorphous solid dis- solubility but also prevented albendazole crystallization in a neu- 248
183 persions dissolved in water [31,32]. These properties along with tral medium for 8 h. The absorption study of orally administered 249
184 the fast dissolution rate of amorphous carriers due to the low ther- albendazole in rabbits with low gastric acidity showed more than 250
185 modynamic stability of amorphous state carriers enhance the drug three times higher bioavailability of HPMC–HPMCP based solid 251
186 solubility and release rate. dispersions compared to physical mixtures. In fact, HPMC and its 252
187 Amorphous carriers can be divided into full synthesis polymers derivatives have been successfully applied in many marketed solid 253
188 and natural products based polymers. The full synthesis polymer dispersion products (Table 1). 254
23 September 2013
255 Some enteric polymers such as HPMCP, HPMCAS, EudragitÒ L in amorphous and crystalline state. All solid dispersions signifi- 319
256 can be used to avoid drug release in the stomach. Since the major- cantly improved the dissolution of ibuprofen and ketoprofen. Inu- 320
257 ity of drug absorption occurs in the small intestine and the fast re- tec SP1 is a derivative of inulin prepared by the reaction between 321
258 lease of drugs in the stomach can cause precipitation due to drug isocyanates and the polyfructose backbone and can be used as an 322
259 supersaturation, the gastric juice resistant polymers may be help- emulsifier in pharmaceutical formulations [52,53]. It was intro- 323
260 ful to improve the in vivo bioavailability of drug. Zhang et al. [40] duced into solid dispersions as a novel carrier in the research of 324
261 prepared amorphous fenofibrate (FB) solid dispersions using solu- Van den Mooter et al. [20] and showed potential in improving drug 325
262 plusÒ, HPMCE5 as carriers for immediate release and HPMCP55, release. 326
263 HPMCAS as carriers for enteric release. The in vitro dissolution test Other surfactants and emulsifiers such as sodium lauryl sulfate 327
264 showed more improvement in dissolution profile of FB-HPMCE5 (SLS) [54], Tween 80 [55,56], d-alpha tocopheryl polyethylene gly- 328
265 and FB-HPMCAS solid dispersions. Although the maximum col 1000 succinate (TPGS 1000) [57], polyoxyethylene hydroge- 329
266 concentration of the drug in the supersaturation dissolution profile nated castor oil [58] and sucrose laurate [59] are used as 330
267 of FB-HPMCE5 and FB-HPMCAS solid dispersions were similar, the additives in solid dispersions. De Waard et al. [60] incorporated 331
268 in vivo pharmacokinetic study in rats showed significant improve- SLS in the sugar glass based solid dispersions and prepared tablets. 332
269 ment in bioavailability of FB-HPMCAS granules in comparison with Physical mixture of SLS and sugar glass based solid dispersions was 333
270 FB-HPMCE5 granules. This was explained by the complete dissolu- also compressed to make standard tablets. The dissolution of tab- 334
271 tion of FB in the proximal small intestine and the stronger effect in lets prepared from solid dispersions in which SLS was incorporated 335
272 remaining drug supersaturation state of the FB-HPMCAS solid was strongly improved compared to standard tablets. It was ex- 336
273 dispersion. plained that SLS interacted with drug and carrier when it was 337
274 Sugar glasses such as trehalose, sucrose and inulin are also used incorporated in solid dispersions; therefore, the dissolution of 338
275 to prepare solid dispersions thanks to their extremely fast dissolu- SLS was prolonged and this helped to maintain the high concentra- 339
276 tion rate. However, the rapid dissolution of carriers can result in a tion of the drug in the near vicinity of the dissolving tablet during 340
277 very high concentration of drugs in the near vicinity of the dissolv- the whole dissolution process, thus preventing the drug precipita- 341
278 ing solid dispersions which leads to precipitation and formation of tion effectively. 342
279 large drug crystals [42]. Inulin dissolves more slowly than sucrose
280 and trehalose because of its oligomeric nature; therefore, the pre- 2.4. Fourth generation 343
281 cipitation and crystallization rate of inulin based solid dispersions
282 dispersed in water is lower than trehalose and sucrose based solid The fourth generation solid dispersion is a controlled release 344
283 dispersions [45]. solid dispersion (CRSD) containing poorly water-soluble drugs 345
with a short biological half-life. CRSD of poorly water-soluble 346
284 2.3. Third generation drugs often requires two targets: solubility enhancement and 347
extended release in a controlled manner. In CRSD, the molecular 348
285 Although the amorphous solid dispersions can enhance drug re- dispersion of poorly water-soluble drugs in carriers will improve 349
286 lease rate, the subsequent supersaturation state of drugs may the drug solubility while water insoluble polymers or swellable 350
287 cause drug precipitation and decrease the drug concentration polymers can be used to retard the drug release in the dissolution 351
288 in vitro or in vivo, thus negatively affecting the bioavailability of medium [61]. The CRSD can deliver an adequate amount of drug 352
289 drugs. This phenomenon is very common, especially with sugar for an extended period of time and thus offer many advantages 353
290 glass based solid dispersions. The drug may also recrystallize from such as improved patient compliance due to reduced dosing fre- 354
291 amorphous state in the preparation process (cooling or solvent re- quency, decreased side effects, more constant or prolonged thera- 355
292 moval) and during storage. In the third generation solid disper- peutic effect for poorly water-soluble drugs [62,63]. The 356
293 sions, the surface active agents or self-emulsifiers are introduced conventional polymers used for retarding the release of poorly 357
294 as carriers or additives and showed significant improvement in water-soluble drugs in CRSD include ethyl cellulose (EC) [62], 358
295 overcoming the above problems such as precipitation and recrys- HPC [28], EudragitÒ RS, RL [61,64], poly(ethylene oxide) (PEO) 359
296 tallization. These surfactants are used as process aids and additives and carboxyvinylpolymer (CarbopolÒ) [65]. These polymers which 360
297 which act to improve the biopharmaceutical performance of the are insoluble or dissolve very slowly in water can sustain the re- 361
298 supersaturation systems. The introduction of surfactants or emul- lease of poorly water-soluble drugs. The CRSD uses these sustain- 362
299 sifiers in solid dispersions improves not only the dissolution profile able polymers or combines these polymers in solid dispersion 363
300 (Fig. 2) but also the physical and chemical stability of drug. In fact, systems or can use other materials having solubilizing capacity 364
301 surfactants with amphiphilic structure can enhance the miscibility and sustaining action. The CRSD have two main mechanisms by 365
302 of drugs and carriers and thus reduce the recrystallization rate of which the drug can be released: diffusion and erosion. Cui et al. 366
303 drugs. Moreover, surfactants or emulsifiers are able to improve [64] prepared sustained-release nitrendipine microspheres having 367
304 the wettability of drugs and prevent the drug precipitation due solid dispersion structure. HPMCP-55 and Aerosil were used as the 368
305 to supersaturation by absorbing to the outer layer of drug particles solid dispersing agents to improve the dissolution of nitrendipine 369
306 or forming micelles to encapsulate drugs. while EudragitÒ RS PO and EC were selected as the retarding agent 370
307 The surfactants used as carriers include poloxamer [46], compr- to control the drug release rate. The bioavailability results in dogs 371
308 itol 888 ATO [47], gelucire 44/14 [48], inutec SP1 [20] and solu- showed the superior prolonged absorption profile and bioavailabil- 372
309 plusÒ [49]. Poloxamer is a very common polymer which has been ity improvement of solid dispersion microspheres compared to the 373
310 used for such a long time in solid dispersions as a carrier or addi- reference tablets (Baypress™) and the conventional tablets. Ohara 374
311 tive while soluplusÒ has just been applied in recent years and et al. [66] investigated the dissolution mechanism of indomethacin 375
312 showed superior performance in hot melt extrusion processes from extended release solid dispersion system with EC and HPMC 376
313 [50]. Ali et al. [51] prepared ibuprofen and ketoprofen solid disper- (1:1). It was concluded that the hydrophobic interaction between 377
314 sions at different mole ratios using poloxamer 407 and 188. FTIR indomethacin and EC occurred under lower pH region and strongly 378
315 indicated the disruption of the ibuprofen, ketoprofen dimer con- delayed the dissolution of indomethacin. Tran et al. [67] prepared 379
316 comitant with hydrogen bond formation between the drug and polyethylene oxide (PEO)-based CRSD containing aceclofenac, 380
317 carrier. Solid dispersions with mole ratio of drug–carrier 2:1 had GelucireÒ 44/14, poloxamer 407 and pH modifier (Na2CO3) for con- 381
318 no drug crystal while at higher drug loading the drug co-existed trolled release of poorly water-soluble drug. The CRSD improved 382
23 September 2013
383 the dissolution profile of aceclofenac with an aid of surfactant and important advantages to become one of the most promising strat- 444
384 pH modifier compared to pure drug and showed retard drug re- egies. Solid dispersions can reduce the drug particle size into 445
385 lease in a zero-order manner due to the water swellable property molecular levels while other conventional particle size reduction 446
386 of PEO. techniques have particle size limit around 2–5 lm, which easily 447
agglomerate in the formulation, dissolution process or during stor- 448
age [69–71]. Novel nanosizing approaches can produce drug nano- 449
387 3. Mechanism of drug release from solid dispersions
crystals in a solid state but the preparation process is quite long, 450
complicated and requires stabilizers as well as special equipments 451
388 There are two main mechanisms of drug release from immedi-
[72]. In solid dispersions, the interaction between the drug and car- 452
389 ate release solid dispersions: drug-controlled release and carrier-
rier prevents the agglomeration of drug particles and the drug is 453
390 controlled release. When solid dispersions are dispersed in water,
released in supersaturation state which is advantageous for rapid 454
391 the carriers often dissolve or absorb water rapidly due to their
absorption. Even when the drug from solid dispersions precipitates 455
392 hydrophilic property and form concentrated carrier layer or gel
due to supersaturation in the dissolution media, the size of precip- 456
393 layer in some cases. If the drug dissolves in this layer and the vis-
itated particles are still in submicron (<1 lm) and the dissolution 457
394 cosity of this layer is high enough to prevent the diffusion of the
rate of these particles is still higher than microparticles prepared 458
395 drug through it, the rate limiting step will be the diffusion of the
by other techniques [23,73]. However, the precipitated drugs 459
396 carrier into the bulk phase and this mechanism is carrier-con-
may also exist in amorphous or different crystalline forms which 460
397 trolled release. If the drug is insoluble or sparingly soluble in the
have lower thermodynamic stability (higher energy state) than 461
398 concentrated layer, it can be released intact to contact with water
drug particles, leading to faster dissolution for in vivo situations. 462
399 and the dissolution profile will depend on the properties of drug
Moreover, solid dispersions can be formulated in solid oral dos- 463
400 particles (polymorphic state, particle size, drug solubility) [22]. In
age forms which are more acceptable for patients than liquid prod- 464
401 fact, these two mechanisms often occur simultaneously because
ucts produced by solubilization method [70,73]. The preparation 465
402 the drug may be partly soluble or entrapped in the concentrated
process of solid dispersions is also more simple and applicable than 466
403 carrier layer. However, these mechanisms help explain the differ-
some other techniques such as salt formation or nanosized prepa- 467
404 ent release behaviors of solid dispersions and figure out the way
ration (nanoparticle, nano-emulsions). 468
405 to improve the dissolution profile of solid dispersions. Numerous
Solid dispersions also have other advantages in improving the 469
406 researches showed the improvement of drug dissolution profile
drug bioavailabilty such as wettability, porosity enhancement 470
407 when the ratio of carriers in solid dispersions was increased
and polymorphic change. The fast dissolution or water absorption 471
408 because the drug was dispersed better and the drug crystallinity
of carrier molecules surrounding drug particles can improve the 472
409 decreased [26]. In these solid dispersions the main release mecha-
drug wettability, especially when surfactants or emulsifiers are 473
410 nism is drug-controlled release. In contrast, other researches dem-
incorporated in solid dispersions. This reduces the risk of agglom- 474
411 onstrated the decrease in drug dissolution rate when the ratio of
eration of drug particles in the dissolution media and increase the 475
412 carrier in solid dispersions was increased [68]. This can be ex-
dissolution rate of drug. Many polymers can act as solubilizers to 476
413 plained by the carrier-controlled mechanism in which the gel or
enhance drug solubility. Solid dispersions also have high porous 477
414 concentrated carrier layer is formed and acts as a diffusion barrier
structure, especially those prepared by solvent method. The fast 478
415 to delay drug release. The release mechanism may also be affected
solvent removal may leave some channels in the solid dispersion 479
416 by the ratio of drug–carrier in solid dispersions. Karavas et al. [44]
structure, thus increasing the porosity, surface specific area and 480
417 prepared felodipine solid dispersions by using different types of
the dissolution rate of drug. Linear polymer based solid dispersions 481
418 PVP, PEG as carriers and concluded that the proportion of the drug
often have higher porosity than reticular polymer based solid dis- 482
419 in solid dispersions determined the mechanism of drug release
persions [74]. Zhang et al. [40] when preparing amorphous FB solid 483
420 which was drug diffusion (through the polymer layer)-controlled
dispersions by thin film freezing techniques as mentioned above 484
421 at low drug contents and drug dissolution-controlled at high drug
also found that the thin film freezing process dramatically in- 485
422 contents. Therefore, in order to improve the dissolution profile of
creased the surface area of the aggregates of FB-polymer composi- 486
423 solid dispersions, it is important to identify the mechanism release
tions by at least 40-times compared to the bulk FB powder and the 487
424 of solid dispersions rather than only focus on the polymorphic
significant increase in surface area facilitated the enhancement of 488
425 state of drugs because in carrier-controlled release solid disper-
dissolution rate and bioavailability of FB. Numerous researches 489
426 sions, the carrier properties such as solubility, viscosity, gel form-
on solid dispersions demonstrated the change in polymorphic state 490
427 ing ability and the ratio of drug–carrier are the key factors
of drugs from crystalline to amorphous form. In general, the reduc- 491
428 affecting the drug dissolution profile.
tion of drug crystallinity will improve the dissolution rate because 492
429 In CRSD, depending on the characteristic of polymers and the
less energy is required to break up the crystal lattice during the 493
430 miscibility of the drug and carrier there are two main mechanisms
dissolution process, thus increasing the drug solubility [33]. The 494
431 by which the drug can be released from the system: diffusion and
polymorphic state of drugs in solid dispersions is mainly 495
432 erosion. If the drugs and polymers are well dispersed in internal
determined by the preparation process and the physicochemical 496
433 structure of solid dispersions, the diffusion of drugs through the
interactions between drug and carrier. 497
434 matrix will be the main mechanism. If the drugs and carriers exist
435 in separated particles, the solid dispersion erosion may become the
436 main mechanism for drug release. In some solid dispersions, both
5. Common problems of solid dispersions 498
437 of these mechanisms can control the drug release at the same time
438 [66].
Despite many advantages in improving dissolution profile of 499
poorly water soluble drugs, the number of commercial products 500
439 4. Advantages of solid dispersions using solid dispersions is limited because of some problems in 501
the preparation process and during storage. The most important 502
440 In comparison with other techniques used to improve bioavail- problem is the recrystallization of drugs from amorphous state 503
441 ability of poorly water soluble drugs such as salt formation, parti- during storage which leads to decreased bioavailability of solid 504
442 cle size reduction (milling or micronization), and solubilization dispersions. The crystallization of drugs involves two steps: 505
443 (cosolvent, micelles, emulsions), solid dispersions show many nucleation followed by crystal growth that requires the diffusion 506
23 September 2013
507 or rearrangement of drug molecules [1]. Therefore, molecular higher miscibility of indoprofen in PVP was explained by hydrogen 570
508 mobility of drugs is the key factor determining the drug physical bonding between the drug and polymer proved by FTIR data. No 571
509 stability. The molecular mobility can be divided into global mobil- hydrogen bond between the griseofulvin and PVP was noticed; 572
510 ity (a-relaxations) which is the molecular rotation, translation for therefore, the author concluded that phase separation rates ob- 573
511 the glass transition and local mobility (b-relaxations) which relates tained were proportional to the drug–polymer interactions and 574
512 to the movement of only a part of a molecule and occurs at a smal- the drug content of the dispersion. In many researches, although 575
513 ler time scale than global mobility [3,75]. At 50 °C below the glass drugs existed in crystalline state in solid dispersions, the in vivo 576
514 transition temperature (Tg), the a-relaxations are negligible and b- bioavailability was increased significantly in comparison with 577
515 relaxations are thought to determine the rate of nucleation and physical mixture. These solid dispersions will not face crystalliza- 578
516 crystallization of amorphous materials [76–78]. The presence of tion problems and thus have good stability [51,84]. 579
517 water often reduces the Tg of amorphous systems due to its plas- The appearance of surfactants and emulsifiers in third genera- 580
518 ticizing effect and thus increases the molecular mobility [79,80]. tion solid dispersions may increase the miscibility of drug–poly- 581
519 The increased temperature also enhances the molecular mobility mer due to their amphiphilic structure and thus reduce the 582
520 and causes recrystallization in solid dispersions. Therefore, the recrystallization rate. The surface active agents can also reduce 583
521 storage temperature and moisture are important factors affecting the process temperature of melting method due to their plasticiz- 584
522 the physical stability of drug. The poor scalability for the purposes ing effect and increase the solubility of drugs and carriers in organ- 585
523 of manufacturing is also the main obstacle for solid dispersions to ic solvents in the solvent method. When solid dispersions are 586
524 be available in the market [6]. dispersed in water, the surface active agents improve drug wetta- 587
525 Furthermore, there are some common problems in the prepara- bility and inhibit the precipitation process by absorbing on the sur- 588
526 tion, formulation and dissolution process that researchers have to face of drug particles or forming micelles encapsulating drugs. 589
527 consider in research and development of solid dispersion products. Mura et al. [85] investigated the effect of anionic surfactants 590
528 These problems include the thermal instability of drugs and carri- including SLS, dioctylsulfosuccinate (DSS) and nonionic surfactant 591
529 ers in the melting method, the solvent residue in the solvent meth- (Tween 60) on the properties of ketoprofen ternary solid disper- 592
530 od, the recrystallization of drugs in solidification and further sions in polyethylene glycol 15,000. Although the binary system 593
531 formulation process, the low in vivo–in vitro correlation, and the (ketoprofen–PEG) showed the dissolution enhancement compared 594
532 precipitation of drugs after dissolving in water due to supersatura- to pure drug, the dissolution profile of solid dispersion was signif- 595
533 tion. Ayenew et al. [81] investigated the effect of compression in icantly improved when the surfactants were incorporated to make 596
534 the tableting process on miscibility of naproxen–PVP K25 solid dis- ternary systems. It was explained by the presence of the surfac- 597
535 persions. FTIR showed that the miscibility in the compositions with tants which improved wettability and decreased surface tension 598
536 30% and 40% (w/w) naproxen is markedly affected by the compres- of drug particles and dissolution medium, leading to the inhibition 599
537 sion process. Compression pressures from beyond 565.05 MPa of drug precipitation. The micellar solubilization effect of surfac- 600
538 induced apparent amorphous–amorphous phase separation. This tant was excluded because the surfactant concentration in the dis- 601
539 was explained by the weakening and/or disruption of intermolec- solution medium was generally below the critical micelle 602
540 ular hydrogen bonding between drug and polymer upon compres- concentration. The crystallinity degree of the ternary systems 603
541 sion. It is important to mention the poor correlation between was also lower than binary system which showed the efficiency 604
542 in vitro dissolution data and in vivo absorption despite the use of of surfactants in improving drug–polymer miscibility. The effec- 605
543 biorelevant in vitro dissolution media in case of poorly water- tiveness of the incorporated surfactants depended on the types of 606
544 soluble drugs [82]. Although SUPAC-based biowaiver is possible surfactants (SDS > DSS > Tween 60) and the solubilizing efficiency 607
545 by FDA in case of BCS Class I, in vivo testing or a clinical assessment of anionic surfactants was higher than the nonionic one. The great- 608
546 would be always needed for a BCS Class II (even III, IV) compound est efficacy of SDS could be due to its high hydrophilic property 609
547 to prove the efficiency of solid dispersions in improving bioavail- and strong solubilizing ability. 610
548 ability of poorly water soluble drugs. In order to prevent the recrystallization of drugs in the solidifi- 611
cation process (cooling, solvent removal) many techniques have 612
been developed to increase the solidification rate such as ultra ra- 613
549 6. Strategies to overcome the common problems of solid pid freezing, spray drying and spray freezing which will be men- 614
550 dispersions tioned below. 615
551 Polymers often have higher glass transition temperature (Tg)

7. Preparation method 616
552 compared to the API so they can decrease the molecular mobility
553 of drug by increasing the Tg of the miscible mixture or by interact-
There are three major preparation methods for solid dispersions 617
554 ing with drug molecules [33,76]. A polymer has to be miscible with
including melting method, solvent method and melting solvent 618
555 drug to prevent the drug recrystallization and the miscibility de-
method (Fig. 3). In fact, the melting method and solvent method 619
556 pends on the molecular interaction between the drug and polymer
are more common than the melting solvent method. 620
557 [17,83]. Hydrogen bonding between the drug and polymer is the
558 main force to increase the solid miscibility and thus hinder phase
559 separation and drug recrystallization. However, many polymers 7.1. Melting method 621
560 are hygroscopic and the water absorbed by polymers may increase
561 molecular mobility. Therefore, selecting a suitable polymer which 7.1.1. Characteristic features, advantages and limitations of melting 622
562 has high Tg, strong interaction with drug and low hygroscopicity method 623
563 is the way to stabilize the physical state of drugs in solid disper- The first solid dispersions for pharmaceutical application were 624
564 sions. Vasanthavada et al. [83] investigated factors influencing so- prepared by melting method or fusion method [21]. In the melting 625
565 lid solubility and phase separation kinetics of drugs in method, the drug and carrier are melted together at a temperature 626
566 griseofulvin–PVP and indoprofen–PVP solid dispersions. Griseoful- above the eutectic point, which is the lowest possible melting 627
567 vin did not exhibit any solid solubility in PVP, whereas a 13% w/w point of the mixture, then the liquid is cooled or solidified by dif- 628
568 indoprofen remained molecularly miscible with the polymer under ferent techniques such as ice bath agitation [16], spreading on 629
569 accelerated stability conditions of 40 °C/69% RH for 3 months. The stainless steel thin layer cooled by air or water [86], putting petri 630
23 September 2013
Preparation method
the miscibility, thus resulting in an inhomogeneous solid disper- 672
sion. This phenomenon can be prevented in some cases by using 673
surfactants. The phase separation can also occur during cooling, 674
as the drug–carrier miscibility changes. Indeed, slow cooling the 675
mixture often produces drugs in crystalline state, while fast cooling 676
Melting Solvent evaporation Melting solvent may yield drugs in amorphous state. This limitation can be con- 677
trolled by using spray congealing technique to quickly solidify 678
melted mixture in cool air. Spray congealing is a process in which 679
a hot molten mixture (solution or suspension of a drug in a molten 680
• Ice bath agitation • Oven drying carrier) is atomized into an environment maintained at tempera- 681
• Thin film cooling • Vacuum drying tures below the carrier melting point [90,91]. The atomization 682
• Liquid nitrogen • Rotary evaporation makes the melted droplets congeal rapidly to form solid particles. 683
• Heating on hot plate
• Spray congealing This method was used in many researches to prepare solid disper- 684
• Spray drying
• Hot-melt extrusion sions [92,93]. 685
• Freeze drying
• MeltrexTM
• Supercritical anti-solvent Another limitation of the melting method is the thermostability 686
• Melt agglomeration • Co-precipitation of the API and the carrier at high temperature. A modified 687
• Electrostatic spinning technique to reduce the drug heating time and the process temper- 688
• Spray freeze drying ature was performed by suspending the API in a previously molten 689
• Ultra-rapid freezing
carrier, instead of heating both drug and carrier at the same time to 690
• Fluid-bed coating
obtain molten mixture. Mehanna et al. [94] applied this technique 691
to prepare tadalafil-PluronicsÒ solid dispersions. PluronicsÒ of var- 692
ious grades was melted at 70 ± 2 °C, followed by the addition of 693
Fig. 3. A branched tree used for the production of solid dispersions. drug powder to the molten carrier and stirring until a homogenous 694
dispersion was formed. The SEM, DSC, PXRD results showed micro- 695
crystalline uniform dispersion of tadalafil in the carrier matrix. 696
631 dishes inside a dessicator [87] and immersion in liquid nitrogen Although the drug was still in crystalline state, the dissolution rate 697
632 [88]. The resultant solid is then crushed, sieved, pulverized to of tadalafil in Pluronic F-127 based solid dispersion significantly 698
633 reduce the particle size or injection molded into dosage forms increased compared to the physical mixture. Several important 699
634 without undergoing milling. The advantage of this method is that modifications of melting method to overcome its limitations con- 700
635 it does not require any solvent. An important prerequisite of this sist of hot-melt extrusion, Meltrex™, and melt agglomeration. 701
636 method is the miscibility of the drug and carrier in the molten state
637 to obtain a homogenous mixture. Therefore, a suitable carrier 7.1.2. Hot melt extrusion 702
638 should shares similar physicochemical properties with the API. In recent years, hot melt extrusion has become one of the most 703
639 PEG and poloxamer are two polymers that are commonly used to common methods for solid dispersion preparation due to its high 704
640 prepare solid dispersions by the melting method. Kolašinac et al. scalability and applicability. In this method, the drug and carrier 705
641 [68] prepared solid dispersions by melting method at a low tem- are simultaneously mixed, heated, melted, homogenized and ex- 706
642 perature (70 °C) using poloxamer P 188 and poloxamer P 407 to in- truded in a form of tablets, rods, pellets, or milled and blended 707
643 crease the solubility and the dissolution rate of desloratadine. Solid with other excipients for different purposes [95]. The intense mix- 708
644 dispersions containing different weight ratio of poloxamers and ing and agitation forced by the rotating screw during the process 709
645 desloratadine were prepared and then were used for the prepara- cause disaggregation of drug particles in the molten polymer, 710
646 tion of immediate release tablet. The results showed that deslorat- resulting in a homogenous dispersion [32]. This process involves 711
647 adine existed in the amorpohous state in solid dipersions and both the transformation of a solid mass of intertwined particles into a 712
648 types of poloxamer significantly enhanced intrinsic solubility of viscous liquid or semisolid mass by heating and intense mixing. 713
649 desloratadine (10–80 times) as well as the dissolution profile of The hot melt extruded systems are composed of drugs, one or more 714
650 desloratadine tablets. Poloxamer P 407 was approximately 4-fold meltable polymers and other additives such as plasticizers and pH 715
651 less effective than poloxamer P 188 as a solubilizer because of its modifiers. The melting rate is mainly affected by the physical and 716
652 higher molecular weight and higher proportion of hydrophobic rheological properties of the polymer. The melting rate is much 717
653 polyoxypropylene segment. The increase in poloxamer ratio over faster when polymers are amorphous and low viscous. Hot melt 718
654 1:1 in solid dispersions decreased intrinsic dissolution rate of desl- extrusion of miscible components may lead to a high trend of 719
655 oratadine because larger amount of poloxamer in solid dispersions amorphous solid dispersion formation, thus improving drug disso- 720
656 provide better conditions for gel layer formation when contacting lution profile. In order to select a suitable polymer for hot melt 721
657 with water, which consequently acts as a diffusion barrier and de- extrusion process, Hansen solubility parameter can be applied to 722
658 lays drug release. The high compression force reduced the dissolu- predict the drug–carrier miscibility [96,97]. Despite some prob- 723
659 tion rate of desloratadine by reducing the porosity of the tablet and lems such as the miscibility of drugs and carriers as well as high 724
660 increasing bonding between poloxamer particles. Different types of local temperatures in the extruder due to high shear forces, hot 725
661 PEG such as PEG 4000 and PEG 6000 were also used as carriers to melt extrusion has considerable advantages for pharmaceutical 726
662 increase the solubility of antiviral thiocarboxanilide UC-781 and applications [98]. An important advantage of the hot melt extru- 727
663 nimodipine in solid dispersions prepared by the melting method sion method compared to other melting methods is the low resi- 728
664 [48,89]. dence time of the drug and carrier at elevated temperature in the 729
665 Despite being frequently applied, the melting method has some extruder which reduces the risk of degradation of thermolabile 730
666 noticeable limitations that can severely impact attempts to en- drugs [23]. This method is also continuous, efficient, easy scale- 731
667 hance the bioavailability of poorly water-soluble drugs. A major up and produce higher thermodynamic stability products than 732
668 disadvantage is that the method can only be applied when the drug other methods [99]. This technology has been successfully applied 733
669 and the carrier are compatible and miscible at the heating temper- to design many drug delivery systems such as immediate and con- 734
670 ature. An incompatibility causes phase separation and the high trolled release tablets, granules, pellets, implants, transdermal 735
671 viscosity of a polymeric carrier in the molten stage can prevent drug delivery systems, ophthalmic ocular inserts [100]. Various 736
23 September 2013
737 references have applied hot melt extrusion for solid dispersion and carriers in solvents. However, their incorporation has to be 800
738 preparation. For instance, fenofibrate solid dispersion with carrier carefully considered, because a large excess may induce a signifi- 801
739 of Eudragit E100 or polyvinylpyrrolidone-vinyl acetate copolymer cant change in the matrix structure. The disadvantage of this meth- 802
740 S630 was prepared by hot melt extrusion technology, which od is that the residual solvent remaining after evaporation process 803
741 resulted in an increase in dissolution rate and oral bioavailability may cause toxicity and complete solvent removal is nearly impos- 804
742 [101]. Hot melt extrusion and its advanced technology, Meltrex™, sible. In addition, residual solvent can also, like water, lower the Tg 805
743 are the most successful ones to prepare solid dispersions with and act to plasticize the system, leading to phase separation due to 806
744 many marketed products such as CesametÒ, RezulinÒ, KaletraÒ the increased mobility of components. The use of solvent mixtures 807
745 (Meltrex™), NovirÒ (Meltrex™) and IsotipÒ (Meltrex™) [102,103]. has been proposed as the way to minimize the problems relating to 808
organic solvents. For example, Kumar [110] used a dioxane–buta- 809
746 7.1.3. Meltrex™ and melt agglomeration nol–water mixture to prepare an amorphous solid dispersion of 810
747 Meltrex™ based on the hot melt extrusion principle is a pat- an opioid antagonist. Other disadvantages of the solvent method 811
748 ented solid dispersions manufacturing process. In Meltrex™ tech- are its large environmental issues, the high cost of production 812
749 nology, the use of a special twin screw extruder and the presence due to the extra facilities required for solvent removal and protec- 813
750 of two independent hoppers allow conveying the extruded mass tion against explosion as well as low scalability. For these reasons, 814
751 continuously throughout the extrusion channel and thus reduce hot melt extrusion is more favorable than solvent method to pre- 815
752 the residence time of the drug (approximately 2 min) in the extru- pare solid dispersions if the stability and bioavailability enhance- 816
753 der as well as avoid thermal stress to the drug and excipient ment of solid dispersions prepared by hot melt extrusion are 817
754 [6,104]. The temperatures of all the barrels are independent and ensured. 818
755 can be accurately controlled from low temperature (30 °C) to high Similar to the melting method, the solidification rate in solvent 819
756 temperature (250 °C) [104]. This technique is suitable for drugs method can determine the physical state of drugs in solid disper- 820
757 which are sensitive to oxidation and hydrolysis because oxygen sions. A fast solidification method is always preferred to guarantee 821
758 and moisture may be eliminated during the process. the amorphous state of drugs. Therefore, there are many methods 822
759 In general, the amorphous solid dispersion prepared by melting developed for fast solvent removal such as heating on a hot plate 823
760 method are soft, sticky and have poor flow properties and poor [62], vacuum drying [111], rotary evaporation [112], spray drying 824
761 compressibility which hinder their applications in a large pharma- [113], freeze drying [38], spray freeze drying [37] and ultra rapid 825
762 ceutical scale of tableting [105]. Melt agglomeration method, in freezing [114]. 826
763 which the carrier acts as a meltable binder, is a feasible method
764 to solve these problems. Melt agglomeration is processed in high 7.2.1. Vacuum drying and rotary evaporation 827
765 shear mixers or rotary processor with the mixture prepared by Phase separation is a challenge that can arise during the solvent 828
766 three ways: adding the molten carrier containing the drug to the removal process. The heating process can increase the molecular 829
767 heated excipients [106,107], adding the molten carrier to a heated mobility resulting in phase separation. Therefore, vacuum drying 830
768 mixture of the drug and excipients [46], or heating a mixture of the and rotary evaporation at a moderate temperature are used to 831
769 drug, carrier and excipients to a temperature within or above the avoid that risk and prevent the degradation of drugs and carriers 832
770 melting range of the carrier [106]. The rotary processor may be at high temperature. After solvent evaporation process, the resul- 833
771 preferable to the high shear mixer in melt agglomeration tech- tant solid dispersions may be stored in a vacuum desiccator for 834
772 nique because the temperature can be more easily controlled and complete removal of residual solvent. Although these methods 835
773 higher binder content can be incorporated in the agglomerates are easy to perform, the processes are quite long. Therefore, the 836
774 [29]. Seo et al. [106] prepared the agglomerates containing solid phase separation and recrystallization of drugs can easily occur 837
775 dispersions of diazepam by melt agglomeration in a high shear during the drying process. 838
776 mixer. This study showed significant increase in dissolution rate
777 of diazepam and a higher dissolution rate was obtained with a low- 7.2.2. Spray drying 839
778 er drug concentration indicating a higher degree of molecular dis- Spray drying is an efficient technology for solid dispersion man- 840
779 persion at the lower concentration. It was concluded that the ufacturing because it permits extremely rapid solvent evaporation 841
780 dissolution rate was affected mainly by the type of meltable binder resulting in fast transformation of an API-carrier solution to solid 842
781 since Gelucire 50/13 gave rise to faster dissolution rate compared API-carrier particles [115]. In this technique, the API-carrier solu- 843
782 to PEG 3000. tion or suspension is transported from the container to the nozzle 844
entrance via a pump system and atomized into fine droplets with 845
783 7.2. Solvent evaporation method (solvent method) large specific surface area. These droplets result in rapid evapora- 846
tion of the solvent and the formation of solid dispersions within 847
784 In the solvent evaporation method, solid dispersion is obtained seconds. The size of the solid dispersion particles prepared by 848
785 after the evaporation of solvent from the solution containing a spray drying can be customized by modulating the droplet size 849
786 drug and carrier [16]. The solvent method has solved main prob- via nozzle to meet the requirements for further processing or 850
787 lems of the melting method relating to the decomposition of drugs applications. The drugs in solid dispersions prepared by spray dry- 851
788 and carriers at high temperature because in the solvent method, ing are often in amorphous state; therefore, the solubility and dis- 852
789 the solvent removal can be performed without heat such as freeze solution rate are significantly increased. Spray drying is one of the 853
790 drying technique. Some polymers hardly used as carriers in the most common techniques used to prepare solid dispersions due to 854
791 melting method due to their high melting point can be applied in the possibility of continuous manufacturing, ease of scalability, 855
792 the solvent method. An important prerequisite of this method is good uniformity of molecular dispersion and cost-effectiveness in 856
793 the sufficient solubility of the drug and carrier in a solvent or co- large scale production with high recoveries (more than 95%) 857
794 solvent [23]. Finding a suitable non-toxic solvent is sometimes dif- [116–118]. Solid dispersion products prepared by spray drying 858
795 ficult because carriers are hydrophilic whereas drugs are hydro- are commercially available such as IncivekÒ and IntelenceÒ [118]. 859
796 phobic [108]. The solvents used in solvent method may include
797 methanol, ethanol, ethyl acetate, methylene chloride, acetone, 7.2.3. Freeze drying 860
798 water. . .and mixtures thereof [109]. Some surfactants such as Freeze drying is an alternative method for drying solid disper- 861
799 Tween 80 and SLS can be utilized to increase the solubility of drugs sions. This method shows promise as a suitable technique for the 862
23 September 2013
863 incorporation of drugs into stabilizing matrices because the drug is critical fluids allow the precise control of the solubilization of 927
864 subjected to minimal thermal stress during the solid dispersion many drugs. When using CO2 as a solvent, the drug and carrier 928
865 formation. This method includes two steps: freezing and lyophili- are dissolved in supercritical CO2 and sprayed through a nozzle 929
866 zation. The freezing rate is very important to control phase separa- into an expansion vessel with lower pressure. The rapid expansion 930
867 tion. The basic process consists of immersing the API-carrier induces rapid nucleation of the dissolved drugs and carriers, lead- 931
868 solution in liquid nitrogen until it is fully frozen and the frozen ing to the formation of solid dispersion particles with a desirable 932
869 solution is then lyophilized [27,119]. The advantage of this method size distribution in a very short time. When supercritical CO2 are 933
870 is the minimized risk of phase separation and the disadvantage is used as anti-solvent, it is introduced into the nozzle simulta- 934
871 that most organic solvents have low freezing temperatures and neously with drug–carrier solution in an organic solvent. When 935
872 do not stay frozen during sublimation. Furthermore, sample tem- the solution is sprayed, the solvent is quickly extracted by the 936
873 perature has to be maintained below the Tg of the frozen concen- supercritical CO2 leading to the precipitation of solid dispersion 937
874 trated fraction when glass formation is required. Therefore, the particles [58]. 938
875 process will take much longer time if low temperature is required
876 for freeze-drying of a sample. In order to obtain an acceptable 7.2.6. Co-precipitation method 939
877 duration for the lyophilization process, the solvent should have a Co-precipitation is a suitable technique to prepare solid disper- 940
878 sufficiently high vapor pressure. sions of poorly water-soluble drugs which have low solubility in 941
commonly used organic solvents and high melting points that can- 942
879 7.2.4. Cryogenic processing techniques not be processed by melting and other solvent methods [128]. In 943
880 Solid dispersions can also be obtained by cryogenic processing this method, a drug and carrier are completely dissolved in an or- 944
881 techniques including spray freeze drying (SFD) and ultra-rapid ganic solvent before adding to an anti-solvent which causes simul- 945
882 freezing (URF). These methods increase the freezing rate compared taneous precipitation of the drug and carrier. The resulting 946
883 to freeze drying technique. SFD allows for a reduction in the pri- suspension is then filtered and washed to remove residual sol- 947
884 mary particle size of drug particles without intense frictional or vents. The co-precipitated material obtained after filtration and 948
885 mechanical forces which can cause degradation of the API through drying is referred to microprecipitated bulk powder (MPD) which 949
886 thermal stress [120]. SFD is a very promising drying technique in is a solid dispersion of the drug and carrier [129]. The polymers 950
887 which the solution of the drug and polymer is sprayed into/on used in co-precipitation method often have pH dependent solubil- 951
888 liquid nitrogen or cold dry air and the frozen droplets are subse- ity such as polymethylacrylate, polymethylmethacrylate, HPMCP, 952
889 quently lyophilized. The large surface area and direct contact with HPMCAS, polyvinyl phthalate and cellulose acetate phthalate while 953
890 the cooling agents result in rapid vitrification, thereby reducing the some solvents such as dimethylacetamide, dimethylformamide 954
891 risk of phase separation to a minimum. It also offers the potential and N-methyl pyrrolidone are mainly used due to their excellent 955
892 to customize the particle size to make it suitable for further pro- solvency power, particularly for high molecular weight polymers 956
893 cessing or applications. SFD usually produces drugs in amorphous [129]. Thanks to the poor solubility of ionic polymers in a specific 957
894 state because the rapid freezing rate can prevent molecular range of pH, the drug and polymer can be simultaneously precipi- 958
895 arrangement into crystalline domains [121–123]. Moreover, in an- tated in water (as anti-solvent) and washed by aqueous solution to 959
896 other research, Van Drooge et al. [124] demonstrated that the drug remove residual organic solvents. The advantage of this method 960
897 stability in SFD solid dispersions is significantly better than that of compared to other methods is that it does not need elevated tem- 961
898 comparable freeze dried solid dispersions due to higher cooling peratures which can cause degradation of the drug or carrier. The 962
899 rate of SFD resulting in more incorporation of the drug into matrix, solvents can be less volatile and can be washed by aqueous solu- 963
900 especially at high drug loads. Another cryogenic process, URF, in- tion to remove organic solvents from the product [130]. Moreover, 964
901 volves the use of a solid cryogenic substrate with thermal conduc- co-precipitation method is applicable in large scale and ZelborafÒ 965
902 tivity between 10 and 20 W/(m K) [114]. In this technique, a drug– is the marketed solid dispersion product prepared by this technol- 966
903 polymer solution is applied to a cryogenic solid substrate and the ogy [131]. It is important to mention that the solvent and anti-sol- 967
904 frozen particles are then collected and removed the solvent by vent mixture used in the precipitation process may act as 968
905 lyophilization [125]. As the supercooling is extremely fast, the plasticizers resulting in high molecular mobility and crystallization 969
906 nucleation of API crystals is minimized or completely prevented, [130]. Therefore, the control of precipitation process and the selec- 970
907 resulting in amorphous morphology after lyophilization [126]. As tion of suitable polymer, solvent and anti-solvent are critical to the 971
908 compared to traditional methods, cryogenic processing techniques success of final products. Dong et al. [132] used HPMC-AS to pre- 972
909 offer more advantages. Spray drying and melting method are not pare solid dispersions of a BCS Class II compound by co-precipita- 973
910 always appropriate for use with thermolabile drugs. However, tion method and hot melt extrusion for comparison. PXRD results 974
911 SFD and URF were performed under sub-ambient conditions and indicated the amorphous state of the drug in both products. 975
912 hence they can avoid heat or air that induces degradation of drugs Although two products have similar true densities, the co-precipi- 976
913 during drying processing. In a recent research described by Badens tation product is more porous and has a larger specific surface area 977
914 et al. [127], SFD and supercritical anti-solvent (SAS) were com- than the HME product which may explain for the faster dissolution 978
915 pared in preparation of solid dispersions containing oxeglitazar. profile of co-precipitation product. 979
916 SFD showed lower crystallinity and higher dissolution rate than
917 SAS. However, SAS is more favorable in terms of time consumption. 7.2.7. Electrostatic spinning 980
Electrostatic spinning (electrospinning) can be considered a 981
918 7.2.5. Supercritical anti-solvent (SAS) combination of solid dispersion technology and nanotechnology. 982
919 SAS method generally uses supercritical carbon dioxide (CO2) as In this method, a drug–polymer solution is placed into a spinneret 983
920 a solubilizing solvent or anti-solvent. When supercritical carbon connected with a microsyringe pump and a high voltage between 5 984
921 dioxide is utilized as a solvent, this method is considered an envi- and 30 kV is applied to the needle tip to induce a charge on the sur- 985
922 ronmentally friendly technique because no organic solvent is re- face of the solution [133]. A fixed electrical potential is also applied 986
923 quired. Supercritical fluids are fluids whose temperature and across a fixed distance between the spinneret and the collector 987
924 pressure are above the critical point. The favorable properties of [134]. When electrical forces overcome the surface tension of the 988
925 gases such as high diffusivity, low surface tension and low viscosity feeding solution at the air interface, polymer jets are ejected 989
926 imparted to liquids through manipulation of the pressure of super- [135]. After coming out, the charged jets go straight for some dis- 990
23 September 2013
991 tance, and then travel a spiral path because of the whipping insta- of crystallinity are importantly characterized. The amount of drugs 1051
992 bility [133]. As the jet accelerates through the electric field, the sol- existing in amorphous state can be calculated indirectly from the 1052
993 vent evaporates rapidly to make fibers at micron or submicron extent of crystallinity in the sample. The crystalline state of drugs 1053
994 diameter which are collected on the screen or a spinning mandril. is commonly characterized by the following techniques: thermo- 1054
995 The collected fibers produce a non-woven fabric, which can be analytical techniques such as Differential Scanning Calorimetry 1055
996 used in oral dosage forms by direct incorporation of the materials (DSC) and Modulated Differential Scanning Calorimetry (MDSC); 1056
997 into a capsule or by further processing such as milling or grinding powder X-ray diffraction (PXRD); Confocal Raman Spectroscopy. 1057
998 [135]. In this process, the diameter and morphology of the fila- Other instrumental techniques such as Fourier Transformed Infra- 1058
999 ments are affected by solution surface tension, the polymer solu- red spectroscopy (FTIR), solid state nuclear magnetic resonance, 1059
1000 tion dielectric constant, feeding rate, the electric field strength, Thermal Gravimetry Analysis (TGA) are used to investigate the 1060
1001 tip-to-collector distance as well as some environmental parame- chemical stability and molecular interaction of the drug and car- 1061
1002 ters such as temperature, humidity and air velocity in the spinning rier. Microscopy techniques such as optical microscopy, transmis- 1062
1003 chamber [134]. The main advantage of this technique relates to the sion electron microscopy (TEM), scanning electron microscopy 1063
1004 extremely high surface area per unit mass of fibers which (SEM) and atomic force microscopy (AFM) are also used to qualita- 1064
1005 facilitates the fast and efficient solvent evaporation leading to tively characterize the crystalline states of drug, the molecular 1065
1006 the formation of amorphous dispersions [136]. Therefore, the dis- miscibility, phase separation and surface morphology of solid 1066
1007 solution of the API incorporated in these fibers is improved signif- dispersions. 1067
1008 icantly by two mechanisms: nanosizing and amorphization [137].
1009 Yu et al. [138] prepared PVP based solid dispersions of acetamino- 8.1. Differential Scanning Calorimetry (DSC) and Modulated 1068
1010 phen using electrostatic spinning and compared with other Differential Scanning Calorimetry (MDSC) 1069
1011 methods. The results showed that electrospun nanofiber-based
1012 solid dispersions had significantly faster dissolution profile com- The basic principle of thermal analytical approaches is the dy- 1070
1013 pared to other casting-film solid dispersions prepared by vacuum namic changes in the solid-state properties of material initiated 1071
1014 drying, freeze drying, and heat-drying. by the heating or cooling process. DSC, the most commonly used 1072
thermal technique for solid dispersion characterization, provides 1073
1015 7.2.8. Fluid-bed coating accurate information about melting point, glass transition temper- 1074
1016 In this method, the drug and carrier are firstly dissolved in a ature as well as the energy changes associated with the phase tran- 1075
1017 solvent. This solution mixture is sprayed through a nozzle onto sitions including crystallization and fusion process. The lack of a 1076
1018 the surface of nonpareil pellet in a fluid-bed coater [139,140]. drug melting peak in the DSC thermogram of a solid dispersion 1077
1019 The solvent is removed by drying airflow and the co-precipitate indicates that the drug exists in an amorphous form. In DSC, the 1078
1020 simultaneously deposited on the surface of nonpareil pellets glass transition endotherm, crystallization exotherm and fusion 1079
1021 [141]. The advantage of this method is that solid dispersion endotherm can also be quantified and used to calculate the degree 1080
1022 granules or pellets can be ready for tableting or encapsulating into of crystallinity [143]. For instance, Urbanetz [30] used DSC to eval- 1081
1023 capsules without further handling. As showed in the researches of uate the remaining amorphous content of a drug in solid disper- 1082
1024 Sun et al. [142], solid dispersions prepared by fluid-bed coating sions during storage conditions. However, the degree of 1083
1025 demonstrated the bioavailability improvement of fenofibrate and crystallinity which is under 2% may not be detected by DSC [23]. 1084
1026 silymarin in vivo. DSC parameters, such as endotherm (DHtr, J/g), was also used to 1085
predict the bioavailability of solid dispersion products by Berndl 1086
et al. [144]. It was concluded that the solid dispersions of itraco- 1087
1027 7.3. Melting-solvent method
nazole improved bioavailability as DHtr < 0.35 J/g and the lower 1088
endotherm of solid dispersions obtained when the higher energy 1089
1028 The melting solvent method is the combination of the melting
inputted during melt extrusion process led to bioavailability 1090
1029 method and the solvent method. In this method, the drugs are
improvement. 1091
1030 dissolved in a suitable solvent and mixed with the molten carrier
Modulated DSC is an advanced thermal technique that can de- 1092
1031 followed by solvent removal and solidification to form solid disper-
convolute the different thermal events obtained from DSC. In 1093
1032 sions. The advantage of this method is that the temperature and
MDSC, a sinusoidal wave modulation is superimposed on top of 1094
1033 the mixing time are lower than melting method, thus protecting
the conventional linear temperature ramp allowing the separation 1095
1034 the drug from thermal degradation. In addition, the carrier in the
of total heat flow in DSC into reversing and non-reversing thermal 1096
1035 molten state is more easily dispersed and dissolved in the solvent
transition [1]. Thermal events such as enthalpic relaxation, evapo- 1097
1036 in comparison with solvent method.
ration, crystallization, thermal decomposition and some other 1098
1037 A branched tree listed the preparation techniques for solid dis-
melting events are distributed in the non-reversing heat flow while 1099
1038 persion is showed in Fig. 1. In fact, the optimal method and tech-
the reversing heat flow includes other melting events and glass 1100
1039 nique for solid dispersion preparation was chosen based on the
transition [145]. The application of this MDSC technique in solid 1101
1040 physicochemical properties of drugs and carriers. In general, spray
dispersion characterization has become very popular due to its 1102
1041 drying and hot melt extrusion are most commonly used due to
advantages such as the improvement of both sensitivity and reso- 1103
1042 their high scalability and applicability.
lution, analysis of complex overlapping transitions, direct mea- 1104
surement of the heat capacity and detection of weak glass 1105
1043 8. Characterization of physicochemical properties transitions compared to standard DSC [146]. As described by Gui- 1106
not and Leveiller [146], MDSC method was successfully used to de- 1107
1044 The dissolution enhancement of poorly water-soluble drugs in tect and quantify low levels of amorphous phase in crystalline drug 1108
1045 solid dispersions can be proven by the standard dissolution meth- through measurements of the heat capacity jump associated with 1109
1046 ods. Other properties of solid dispersions such as the physical the amorphous phase glass transition. Ghosh et al. [145] tried to 1110
1047 states of drugs, the drug–carrier interaction and the physical and develop a stable amorphous solid dispersion of a poorly water-sol- 1111
1048 chemical stability of drugs should also be evaluated. Consequently, uble and highly thermal sensitive compound by hot melt extru- 1112
1049 many instrumental and analytical techniques are applied to mea- sion. Preliminary MDSC studies showed that propylene glycol 1113
1050 sure these properties. The crystalline state of drugs and the degree was the most suitable plasticizer which could provide single phase 1114
23 September 2013
1115 solid dispersion of the API with various polymers and also facilitate process and the biocompatibility of loratadine and PVP in solid dis- 1175
1116 low processing temperatures. The molecular miscibility, recrystal- persions. The results showed that loratadine was stable up to 1176
1117 lization and phase separation of solid dispersions after preparation 203 °C at which it started losing mass. The thermoanalytical curves 1177
1118 and under accelerated stability conditions were characterized by of solid dispersions and their components were not significant dif- 1178
1119 MDSC. In this study, a single Tg of solid dispersions showed molec- ferent, which suggested that chemical interactions accelerating 1179
1120 ular miscibility and a new Tg detected by MDSC indicated phase drug or polymer degradation did not occur. 1180
1121 separation. The solid dispersion system was physically stable if Physicochemical characterization of solid dispersions is essen- 1181
1122 no re-crystallization peaks were observed. tial to evaluate the pharmaceutical applicability of solid disper- 1182
sions and thoroughly understand the pharmaceutical 1183
1123 8.2. Powder X-ray diffraction (PXRD) mechanisms of drug dissolution enhancement and physicochemi- 1184
cal stability. Therefore, an ongoing development of new and ad- 1185
1124 PXRD is the most widely used method to identify and character- vanced characterization techniques in solid dispersion area is 1186
1125 ize the crystalline state of drugs in solid dispersions. This method very necessary. 1187
1126 can detect material with long-range order as well as expose sharp
1127 diffraction peaks that indicate crystalline compound with charac-
1128 teristic fingerprint region. Thanks to the specificity of the finger- 9. Future perspectives and strategies 1188
1129 print, the drug crystallinity can be separately identified from the
1130 carrier crystallinity and thus can differentiate the amorphous state Solid dispersions have generated much interest from pharma- 1189
1131 and crystalline state of drugs in solid dispersions. However, the ceutical scientists because of the increasing number of drug candi- 1190
1132 crystallinities under 5–10% fraction may not be detected by PXRD dates which is poorly water soluble and the recent advances on 1191
1133 [23]. this area. Although solid dispersions have been investigated for 1192
such a long time, some novel carriers, additives and new prepara- 1193
1134 8.3. Fourier Transformed Infrared spectroscopy (FTIR) tion, characterization techniques have just been applied in recent 1194
years. This brings new hope to develop more solid dispersion prod- 1195
1135 FTIR is a common technique used to investigate the intermolec- ucts in the future. Recent advances on solid dispersion area can be 1196
1136 ular interaction and drug–carrier compatibility because it can divided into four main issues: (i) applying new carriers, (ii) adding 1197
1137 detect the physical and chemical reaction between drug and car- new additives such as surfactants, superdisintegrants and pH 1198
1138 rier. Hydrogen bonding between drugs and carriers which is very modifiers, (iii) developing novel preparation and characterization 1199
1139 important to explain the physical state and the stability of drugs methods, (iv) elucidating the thermodynamic mechanism of many 1200
1140 in solid dispersions can also be identified by FTIR. Miyazaki et al. processes in the preparation, formulation, dissolution and storage 1201
1141 [39] studied the crystallization rates of nitrendipine (NTR) enanti- stage. These issues are interrelated and will be continuously inves- 1202
1142 omers in the presence of HPMC, HPMCP and PVP. FTIR results indi- tigated in the coming time. 1203
1143 cated that PVP interacted with NTR through hydrogen bonding at To broaden and optimize the various carriers used in solid dis- 1204
1144 the NH moiety of NTR, and almost the same degrees of shift in persions, several studies have introduced new carriers while many 1205
1145 wavenumber for NH stretching suggested a similar strength of other studies utilize more than two polymers as carriers to com- 1206
1146 hydrogen bonding interaction for enantiomers: ()NTR and bine the advantages of each polymer. Some novel carriers used in 1207
1147 (+)NTR. Therefore, similar degree of physical stability between recent years are soluplusÒ, inutec SP1 or KollicoatÒ IR. Lin et al. 1208
1148 ()NTR and (+)NTR was observed in PVP based solid dispersions [149] synthesized nano-sized flake carboxymethyl cassava starch 1209
1149 whereas the overall crystallization rate and the nucleation rate of (CMCS) to prepare solid dispersions loading acetylsalicylic acid. 1210
1150 (+)-NTR were lower than those of ()NTR in HPMC or HPMCP The results suggested that nano-sized CMCS based solid disper- 1211
1151 based solid dispersions because of stereoselective interaction be- sions had much better dispersion capability for the drug than the 1212
1152 tween enantiomers and these carriers. The hydrogen bonding be- normal CMCS and micro-sized CMCS based solid dispersions. The 1213
1153 tween PVP and NTR also explained for the lower growth rate of dissolution rate of nano-sized CMCS based solid dispersions was 1214
1154 NTR crystal in PVP based solid dispersions compared to HPMC considerably higher than that of pure drug. Al-Obaidi et al. [150] 1215
1155 and HPMCP based solid dispersions. investigated the impact of the third polymer on the physical stabil- 1216
ity of drugs in binary solid dispersions. Poly[N-(2-hydroxypro- 1217
1156 8.4. Thermal Gravimetry Analysis (TGA) pyl)methacrylate] (PHPMA) was added to drug–PVP solid 1218
dispersions because it can form hydrogen bonds with drugs (gris- 1219
1157 TGA is a method of thermal analysis that measures the weight eofulvin, progesterone, phenindione) while PVP cannot. The stabil- 1220
1158 change as a function of time and temperature, thereby providing ity results showed that the ternary solid dispersions crystallized 1221
1159 information about the stability of a material and the compatibility more slowly than binary solid dispersions. It was concluded that 1222
1160 of different materials in a solid dispersion mixture. This method the incorporation of a bridging polymer which can form hydrogen 1223
1161 can provide useful information about the stability of drugs and car- bonds with the API and the second polymer can improve signifi- 1224
1162 riers as well as the chemical and physical processes in solid disper- cantly the stability of amorphous drug in immiscible binary solid 1225
1163 sions to decide the preparation method and the processing dispersions. 1226
1164 parameters for solid dispersion preparation. Other common appli- Many novel additives are also added in solid dispersions to 1227
1165 cations in the pharmaceutical sciences include the determination increase the solubility and the stability of API. These additives in- 1228
1166 of moisture and solvent content as well as decomposition, vapori- clude novel surfactants, superdisintegrants, and pH modifiers 1229
1167 zation or sublimation temperatures [147]. However, this technique [151–153]. Szu } ts et al. [59] incorporated sucrose laurate into gem- 1230
1168 is not effective for materials that do not exhibit a weight change fibrozil-PEG6000 solid dispersions. The results showed that the 1231
1169 during degradation and some processes which do not involve the presence of the novel surfactant did not influence the solid-state 1232
1170 loss of mass. Similar to DSC method, TGA results are changeable characteristics of the API significantly. The dissolution of gemfibro- 1233
1171 and depend on the conditions of sample and experimental process zil from the ternary solid dispersion systems was markedly 1234
1172 which is difficult to compare the work of one researcher to another improved compared to the binary solid dispersion systems. It is 1235
1173 [147]. Frizon et al. [148] used TGA method to check the thermal important to notice that two-thirds of poorly water-soluble drugs 1236
1174 stability of loratadine in the temperature range of the preparation have pH-dependent solubility. Accordingly, pH modifiers can be 1237
23 September 2013
1238 proposed as a promising and important approach to improve the help to completely elucidate the structure and dissolution mech- 1301
1239 solubility of such drugs in solid dispersions. Tran et al. [154] anism of solid dispersions in the near future. This can lead to an 1302
1240 proved that the alkalizers in PEG 6000 based solid dispersions syn- optimal selection of carriers and preparation methods for each 1303
1241 ergistically enhanced dissolution of telmisartan, a weak acid, not poorly water-soluble drug and thus will overcome the bioavail- 1304
1242 only by modulating the micro-environmental pH (pHM), but also ability problems of drugs as well as the stability and scalability 1305
1243 by changing drug crystallinity to an amorphous form via molecular problems of solid dispersions. 1306
1244 interactions. Srinarong et al. [155] showed that the dissolution rate
1245 was more increased when the superdisintegrant was incorporated Acknowledgements 1307
1246 in solid dispersions than when it was physically mixed with the
1247 solid dispersions to prepare tablets. The dissolution rate enhance- This work was supported by the Korean Health Technology R&D 1308
1248 ment which was explained by the prevention of drug recrystalliza- Project, Ministry for Health and Welfare (A092018). 1309
1249 tion during dissolution process was strongly dependent on the
1250 type of superdisintegrants. References 1310
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EJPB 11503 No.

of Pages 15, Model 5G

European Journal of Pharmaceutics and Biopharmaceutics xxx (2013) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics

41 1. Introduction development such as salt formation [7], prodrug formation [8], 63

0939-6411/$ - see front matter Ó 2013 Published by Elsevier B.V.

Table 1 carrier to form eutectic mixture with sulphathiazole. In crystalline 112

Poorly water soluble drug

+CC +AP +SFP + WIP or SP

- Low dissolution - Dissolution rate - Highest dissolution - Dissolution rate

includes povidone (PVP) [33], polyethylene glycol (PEG) [34], 189

551 Polymers often have higher glass transition temperature (Tg)

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