Characterization of Amorphous Solid Dispersion of Pharmaceutical Compound with Ph-Dependent Solubility Prepared by Continuous-Spray Granulator

pharmaceutics

Article Characterization of Amorphous Solid Dispersion of Pharmaceutical Compound with pH-Dependent Solubility Prepared by Continuous-Spray Granulator

Ryoma Tanaka 1,2, Yusuke Hattori 1,3,4, Yukun Horie 3, Hitoshi Kamada 5, Takuya Nagato 5 and Makoto Otsuka 1,3,4,*

1 Graduate School of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo, Tokyo 202-8585, Japan; [email protected] (R.T.); [email protected] (Y.H.) 2 Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA 3 Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo, Tokyo 202-8585, Japan; [email protected] 4 Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo, Tokyo 202-8585, Japan 5 Research & Development Department, Technical Division, Powrex Corporation, 5-5-5 Kitagawara, Itami, Hyogo 664-0837, Japan; [email protected] (H.K.); [email protected] (T.N.) * Correspondence: [email protected]; Tel./Fax: +81-42-468-8658

Received: 21 February 2019; Accepted: 1 April 2019; Published: 3 April 2019

Abstract: A continuous-spray granulator (CTS-SGR) is a one-step granulation technology capable of using solutions or suspensions. The present research objectives were, (1) to reduce the manufacturing operations for solid dosage formulations, (2) to make amorphous solid dispersion (ASD) granules without pre-preparation of amorphous solids of active pharmaceutical ingredients (API), and (3) to characterize the obtained SGR granules by comprehensive pharmaceutical analysis. Rebamipide (RBM), a biopharmaceutical classiﬁcation system class IV drug, that has low solubility or permeability in the stomach, was selected as a model compound. Five kind of granules with different concentrations of polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA) were prepared using a one-step SGR process. All of the SGR granules could be produced in amorphous or ASD form and their thermodynamic stability was very high because of high glass transition temperatures (>178 ◦C). They were unstable in 20 ◦C/75%RH; however, their stability was improved according to the proportion of polymer. The carboxy group of RBM was ionized in the granules and interactions appeared between RBM and PVP-VA, with the formation of an ASD conﬁrmed and the solubility was enhanced compared with bulk RBM crystals. The SGR methodology has the possibility of contributing to process development in the pharmaceutical industry.

Keywords: amorphous; solid dispersion; molecular complex; rebamipide; polymer; interaction; stability; characterization; continuous processing; granulation; process development

1. Introduction Among recently developed pharmaceuticals, many synthesized candidate drug compounds have a low bioavailability, due to their low aqueous solubility and/or permeability [1]. These issues influence discovery stage studies and lead to delays in the development of new drugs. According to the biopharmaceutical classification system (BCS), the drug dissolution profile and solubility of the solid-state form are major factors and they influence gastrointestinal permeability, bioavailability, and clinical response [2]. Hence, it is necessary to improve bioavailability by enhancing the solubility of poorly water-soluble drug compounds by making the most of pharmaceutical

Pharmaceutics 2019, 11, 159; doi:10.3390/pharmaceutics11040159 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, 159 2 of 13 Pharmaceutics 2019, 11 FOR PEER REVIEW 2 technologyof poorly water-soluble [3,4]. The main drug methodologies compounds reported by making to achieve the most this of include pharmaceutical alteration oftechnology the solid-state [3,4]. byThe amorphization main methodologies [5], increasing reported the particle to achieve surface th areais byinclude size reduction alteration [6 ],of and the the solid-state formation ofby pharmaceuticalamorphization molecular[5], increasing complexes the particle [7,8]. surface area by size reduction [6], and the formation of pharmaceuticalAmong these, molecular amorphous complexes solid dispersion [7,8]. (ASD) is a representative of amorphous molecular complexesAmong [9, 10these,]. Generally, amorphous ASD solid is a soliddispersion of a polymer-based (ASD) is a representative material involving of amorphous a homogeneously molecular dispersedcomplexes active [9,10]. pharmaceutical Generally, ASD ingredient is a solid of (API) a polymer-based molecules in material a disordered involving state. a homogeneously In some cases, adispersed complex betweenactive pharmaceutical more than two ingredient APIs is dispersed (API) molecules in a polymer in a materialdisordered [11 state.,12]. TheIn some amorphous cases, a statecomplex of a compound between more is more than unstable two APIs without is disperse long-ranged in a order, polymer compared material with [11,12]. the crystal The amorphous state [13]. Thestate use of of a compound amorphization is more or disruption unstable without of the crystal long-range lattice order, increases compared the solubility with the and, crystal consequently, state [13]. leadsThe touse improved of amorphization bioavailability. or disruption As an advantage of the of crystal the ASD lattice system, increases the presence the solubility of a polymer and, canconsequently, stabilize an leads amorphous to improved API. Some bioavailability. studies on As ASDs an advantage have investigated of the ASD API-polymer system, the interactions presence of anda polymer relationships can stabilize [14,15], an manufacturing amorphous API. process Some developmentstudies on ASDs [16, 17have], and investigated other factors API-polymer [18–20]. Theinteractions preparation and ofrelationships an ASD can [14,15], be chosen manufacturing dependent process on the development nature of the[16,17], drug, and for other example, factors the[18–20]. melting The method preparation [21,22 of] an and ASD the can solvent be chosen method dependent [23,24]. on These the nature preparations of the drug, are necessary for example, to providethe melting the final method product [21,22] of ASD and formulations,the solvent method but the [23,24]. manufacturing These preparations unit operation are cutbacks necessary are to idealprovide from the the final viewpoint product of of high-level ASD formulations, quality control but the and manufacturing cost saving in unit the recentoperation pharmaceutical cutbacks are industry.ideal from In the addition, viewpoint an accomplishment of high-level quality for high control drug and loading cost granulessaving in orthe tablets recent is pharmaceutical difficult with ASDindustry. formulations In addition, because an accomplis of the necessityhment for for high high drug concentrations, loading granules such or as tablets 70−80%, is difficult of polymer with carriersASD formulations to enhance thebecause solubility, of the stability, necessity and for drug-polymer high concentrations, interaction such [ 25as,26 70].−80%, Polymers of polymer have beencarriers used to extensivelyenhance the tosolubility, fabricate stability, ASDs; and however, drug-polymer the formation interaction of stable [25,26]. ASDs Polymers requires have high been polymerused extensively concentrations, to fabricate limiting ASDs; their however, use with low-dosethe formation APIs. of Therefore, stable ASDs considering requires an high alternative polymer methodologyconcentrations, for solidlimiting dosage their formulations, use with low-dose ASD granules APIs. with Therefore, high drug considering loading, using an restrictedalternative manufacturingmethodology for processes, solid dosage may be formulations, suitable. ASD granules with high drug loading, using restricted manufacturingA continuous-spray processes, granulator may be suitable. (CTS-SGR) provides a one-step granulation method from solution or suspension.A continuous-spray The SGR method granulator can be divided(CTS-SGR) into theprovides following a one-step three processes granulation (Figure method1): Granule from nucleationsolution or by suspension. spray drying, The layering SGR method granulation can be by divided continuous into spray,the following and product three collection processes using (Figure a size1): classificationGranule nucleation system. by A two-fluidspray drying, spray layering nozzle isgranulation placed vertically by continuous at the bottom. spray, The and SGR product also hascollection side air using nozzles, a size which classification act to brush system. the adhered A two-fluid powder spray off the nozzle face ofis theplaced wall, vertically to maintain at the a continuousbottom. The flowable SGR also state has in side the air SGR. nozzles, The SGR which system act to resembles brush the anadhered ordinary powder spray off drier the andface fluidof the bedwall, granulation, to maintain which a continuous together flowable result in state layering in the granulation SGR. The [SGR27,28 system]. The granuleresembles size an ofordinary spray dryingspray anddrier fluid and bedfluid granulation bed granulation, depends which on the together particle result size in in the layering suspension granulation sample, [27,28]. the nozzle The orificegranule diameter, size of spray and the drying airflow. and However,fluid bed granulatio spray dryingn depends granulation on the may particle have size technical in the suspension problems, suchsample, as the the homogeneity nozzle orifice of thediamet producter, and [29 ].the Additionally, airflow. However, layering spray granulation drying requiresgranulation core may particles have astechnical a seed for problems, the granule such in as order the homogeneity to obtain the of comparatively the product [29]. large Additionally, size granules layering in general. granulation Thus, therequires formation core a particles granule withas a highseed drug for the loading granule is difficult in order because to obtain of the the concentration comparatively of the large seed size in thegranules granule in [ 30general.]. On the Thus, other the hand, formation SGR provides a granule enhanced with high handling, drug loading such asis thedifficult flowability because of of bulk the powderconcentration by layering of the granulation seed in the without granule core [30]. particles, On the other and can hand, prepare SGR uniformlyprovides enhanced spherical granuleshandling, untilsuch the as desiredthe flowability granule sizeof bulk and shapepowder is reached.by layering granulation without core particles, and can prepare uniformly spherical granules until the desired granule size and shape is reached.

FigureFigure 1. 1.The The circulation circulation system system of of a a continuous-spray continuous-spray granulator granulator (CTS-SGR). (CTS-SGR).

Pharmaceutics 2019, 11, 159 3 of 13 Pharmaceutics 2019, 11 FOR PEER REVIEW 3

Rebamipide (RBM), a gastroprotective agent prescribed for gastric ulcer and gastritis patients, Rebamipide (RBM), a gastroprotective agent prescribed for gastric ulcer and gastritis patients, is a weakly acidic BCS class IV drug that is insoluble in acid conditions. However, dissolution in a is a weakly acidic BCS class IV drug that is insoluble in acid conditions. However, dissolution low pH environment is needed because the precise mechanisms of RBM involve increasing gastric in a low pH environment is needed because the precise mechanisms of RBM involve increasing mucosal prostaglandin and gastric mucus production and the site of action of RBM is the stomach gastric mucosal prostaglandin and gastric mucus production and the site of action of RBM is the [31]. Commercial RBM tablets contain 100 mg of the API and the prescribed dosage is three times per stomach [31]. Commercial RBM tablets contain 100 mg of the API and the prescribed dosage is three day. The current study aimed to combine a high API loading formulation and enhancement of the times per day. The current study aimed to combine a high API loading formulation and enhancement solubility of RBM by specific manufacturing processes. For the purpose of achieving this, ASD of the solubility of RBM by speciﬁc manufacturing processes. For the purpose of achieving this, granules were prepared using SGR as a one-step method for producing high drug loading granules. ASD granules were prepared using SGR as a one-step method for producing high drug loading Five types of granules with different concentrations of polymers (0%, 5%, 10%, 20%, and 30% as granules. Five types of granules with different concentrations of polymers (0%, 5%, 10%, 20%, and 30% weight ratio) were prepared by SGR. The physical properties, stability, thermal behavior, molecular as weight ratio) were prepared by SGR. The physical properties, stability, thermal behavior, molecular state, and solubility of the obtained SGR samples were investigated. Comprehensive identification state, and solubility of the obtained SGR samples were investigated. Comprehensive identiﬁcation was performed to understand the characteristics of the granules and expand the possibility of SGR was performed to understand the characteristics of the granules and expand the possibility of SGR as as a process development. a process development.

2. Materials and Methods

2.1. Materials RBM of pharmaceutical grade was kindly provided by Ohara Pharmaceutical (Shiga, Japan, Japan, Figure2 2).). SodiumSodium hydroxidehydroxide (NaOH)(NaOH) asas anan alkylating agent was purchased from FujiﬁlmFujifilm WakoWako PurePure Chemical (Osaka, Japan). Polyvinylpyrrolidone/vinyl acetate acetate copolymer copolymer (PVP-VA; (PVP-VA; Kollidon Kollidon®® VA64,VA64, Figure 22)) asas aa carriercarrier waswas aa generousgenerous giftgift fromfrom BASFBASF (Ludwigshafen,(Ludwigshafen, Germany).Germany). AsAs thethe additivesadditives forfor the tablets, magnesium aluminometaaluminometa silicates (MAS; Neusilin® NS2N)NS2N) was a gift from Fuji Chemical Industry (Wakayama, Japan)Japan) andand croscarmellosecroscarmellose sodiumsodium (CCS;(CCS; KiccolateKiccolateTMTM)) and and magnesium magnesium stearate stearate (Mg-St) werewere purchased purchased from from Asahi Asahi Kasei Kasei Chemicals Chemic (Tokyo,als (Tokyo, Japan) Japan) and Fujiﬁlm and Fujifilm Wako Pure Wako Chemical, Pure Chemical,respectively. respectively. All other chemicals All other chemicals were commercially were commercially available productsavailable ofproducts analytical of analytical grade. grade.

Figure 2. Chemical structures of rebamipide with atom numbering and polyvinylpyrrolidone/vinyl Figureacetate 2. copolymer Chemical (Kollidon structures® VA64).of rebamipide with atom numbering and polyvinylpyrrolidone/vinyl acetate copolymer (Kollidon® VA64). 2.2. Granule Preparation Using a Continuous-Spray Granulator 2.2. Granule Preparation Using a Continuous-Spray Granulator Table1 shows the summarized liquid formulation for spraying using SGR. Firstly, RBM, PVP-VA, and NaOHTable 1 totaling shows 200the gsummarized were dissolved liquid in 1800 formulation g of purified for spraying water at 80using◦C, withSGR. stirring. Firstly, AtRBM, this PVP- time, VA,the molarand NaOH ratio oftotaling REB and 200 NaOH g were was dissolved fixed at in 1:1 1800 and g PVP-VAof purified in Runswater 1 −at5 80 accounted °C, with stirring. for 0%, 5%,At 10%,this time, 20%, the and molar 30% as ratio the of weight REB and ratio. NaOH Then, was the samplefixed at solutions 1:1 and PVP-VA were fed in into Runs the 1 SGR−5 accounted (CST-SGR-01 for without0%, 5%, 10%, size classification20%, and 30% system; as the Powrex,weight ratio. Hyogo, Then, Japan) the atsample a rate solutions of 10−15 were mg/min fed into and the sprayed SGR (CST-SGR-01using a two-fluid without nozzle size with classification the following syst conditions:em; Powrex, Atomizing Hyogo, air Japan) rate wasat a 40–80 rate of NL/min, 10−15 mg/min inlet air andtemperature sprayed wasusing 75 a◦ C,two-fluid and running nozzle time with was the 120–150 following min. conditions: Atomizing air rate was 40–80 NL/min, inlet air temperature was 75 °C, and running time was 120–150 min.

Pharmaceutics 2019, 11, 159 4 of 13

Table 1. Materials used for preparing granules using SGR.

1 2 3 4 Batch RBM PVP-VA NaOH H2O Total No. (g) (g) (g) (g) (g) 1 179.65 0 20.35 1800 2000 2 170.67 10 19.33 1800 2000 3 161.68 20 18.32 1800 2000 4 143.72 40 16.28 1800 2000 5 125.75 60 14.25 1800 2000 1 Rebamipide, 2 Polyvinylpyrrolidone/vinyl acetate copolymer, 3 Sodium hydroxide, 4 Water.

2.3. Physical Property Measurements A scanning electron microscope (SEM; JSM-6510LV, JEOL, Tokyo, Japan) was used to characterize the particle state and morphology. Granule samples were sprinkled onto a carbon tape and coated with carbon by a JEC-560 (JEOL). The acceleration voltage, magnification, and working distance were 1.0 kV, ×500, and 8 mm, respectively. Dried particle size distribution was investigated using a laser light scattering particle analyzer (Mastersizer 3000E with Aero M, Malvern Panalytical, Malvern, UK). Data analysis was done based on algorithms utilizing Mie scattering theory for non-spherical materials. The results were represented as mass median diameter (D50) with a standard deviation of (n = 5). The angle of repose (AR) was evaluated using a modified tilting method [32]. Approximately 30 mg of the granule sample was fed into a sample holder. Then, the holder was slowly tilted until the sample began to slide and the angle of the tilt was measured. The results were described as the mean angle of repose with a standard deviation of (n = 30). The bulk density 1 (ρB) was measured by filling a graduated cylinder (50 mL) with a certain amount of each sample, the height of sample was approximately 10 mm. Additionally, the tapped density (ρT) was evaluated by tapping down each sample in the cylinder, the tapping was repeated 70 times, and the value of the Hausner ratio (HR) and Carr index (CI) were calculated using the following equations: ρ HR = T (1) ρB ρ CI(%) = 100 1 − B (2) ρT where B and T are bulk and tapped samples, respectively [33,34]. The results were shown as mean values with a standard deviation of (n = 3).

2.4. Stability Testing at Different Humidities by X-Ray Diffractometry In order to compare the stability of the amorphous state of RBM in each granule type, 4 g of each sample was placed into containers at 30% RH or 75% RH, with an ambient temperature ca. 20 ◦C, for the speciﬁed time periods (6 months at maximum). The samples were promptly measured by X-ray diffraction (XRD) upon removal of the lid at each time point. The XRD pattern of each sample was collected using RINT-Ultima III (Rigaku, Tokyo, Japan) with Cu Kα radiation (40 kV × 40 mA). The diffraction angle range was from 5◦ to 45◦ in 2-theta, with a step of 0.02◦ and scanned at 15◦/min. Relatively large granules were ground using manual grinding in an agate mortar for adequate XRD analysis.

2.5. Thermal Analysis A differential scanning calorimeter (DSC7000X, Hitachi, Tokyo, Japan) was used for investigating the thermal behavior of granule samples. An approximately 5 mg sample was placed in an aluminum DSC pan. All the measurements were done under a dry nitrogen purge at 30 mL/min and heated from 25 ◦C to 350 ◦C at a rate of 5 ◦C/min. For the purpose of identiﬁcation of the glass Pharmaceutics 2019, 11, 159 5 of 13

transition temperature (Tg), DSC was operated in the modulated mode with the following conditions: Temperature modulation was ±3 ◦C, the repetition rate was 0.2 Hz, and the heating rate was 5 ◦C/min. The value of the glass transition of a binary system was predicted using the following Couchman−Karasz equation: ◦ w1Tg1 + Kw2Tg2 Tg calc( C) = (3) w1 + Kw2

∆Cp2 K = (4) ∆Cp1 ◦ where Tg calc is the theoretical glass transition ( C), w1 and w2 are the weight fractions of each component, Tg1 and Tg2 are their glass transitions, and ∆Cp1 and ∆Cp2 are the change in speciﬁc heat capacity at the glass transition [35,36]. Additionally, a positive difference between the measured and calculated glass transition temperatures was obtained as the characteristic parameter of interaction.

2.6. Fourier Transformed Infrared Spectroscopy Infrared (IR) spectra were accumulated using a Fourier-transform IR spectrometer (FT/IR-4100, Jasco, Tokyo, Japan). The spectral data were collected by powder diffuse reﬂectance using KBr powder, with 64 scans at 8 cm−1 resolution.

2.7. Tablet Preparation and Dissolution Testing A mixture of resulting granules with specific amounts of PVP-VA, 7.2 mg of MAS (3.6%), and 10.0 mg of CCS (5.0%) was blended with 1.0 mg of Mg-St (0.5%) just before tableting. Each formulation ratio of RBM per tablet was adjusted to the same amount as commercial Mucosta® (114.2 mg as a total API). Additionally, the PVP-VA amount depended on each batch (54.5 mg as total PVP-VA). Specifically, the amounts in batch No. 1−5 granules and additional PVP-VAs in tablets were 127.2 mg (63.6%) and 54.6 mg (27.3%), 136.4 mg (68.2%) and 45.4 mg (22.7%), 145.4 mg (72.7%) and 36.4 mg (18.2%), 163.6 mg (81.8%) and 18.2 mg (9.1%), and 181.8 mg (90.9%) and 0 mg (0.0%), respectively. The mixture was compressed using 8 mm flat-faced punches in a single stroke tablet press (Handtab-100, Ichihashi Seiki, Kyoto, Japan). The tablet weight and hardness were 200 mg and 40 N (60–80 MPa compression pressure), respectively. Dissolution testing of tablets was carried out in 900 mL water as the test medium (37.5 ± 0.5 ◦C) using an NTR-3000 apparatus with a paddle speed of 50 rpm (Toyama Sangyo, Osaka, Japan) and a S-2450 spectrophotometer (Shimadzu, Kyoto, Japan). In addition, granule dissolution testing was demonstrated in 900 mL of acidic aqueous solution (pH 1.2 buffer; 37.5 ± 0.5 ◦C) using a DT-610 apparatus with 100 rpm (Jasco) and a V-530 spectrophotometer (Jasco) because of the low solubility of RBM in an acidic medium. The concentration of API during these tests was determined using a UV/VIS spectrophotometer at 327 nm. The mean values and standard deviations with time were calculated (n = 3).

3. Results and Discussion

3.1. Morphology and Physical Properties RBM granules, in a dry state, were prepared by SGR. Figure3 shows SEM images of the obtained samples, which provided insights into the morphology and approximate particle size. The particle size of the 0% PVP-VA sample was the smallest and formed microspheres similar to a spray dried sample, whose size would become the nuclei of the granule. Proportionally to the concentration of PVP-VA, the size of granules increased and the surface became smoother because of the high concentration of polymeric carrier presence as a binder. The 30% PVP-VA sample appeared as heavy and dense granules and the surface rarely had pores, because layering granulation was carried out by continuous spraying of the polymer. In addition, the repeating side airs broke the surface roughness of granules Pharmaceutics 2019, 11, 159 6 of 13 and the spray fluid was extended at the granule surface with drying. Therefore, granule spheroidizing wasPharmaceutics performed. 2019, 11 TableFOR PEER2 shows REVIEW a summary of the physical properties of the samples. The bulk6 density (ρB) and tapped density (ρT) increased with layering and the flowability was also enhanced. Thesesamples. prepared The bulk granules density tended () and to tapped become density denser ( with) increased SGR and with a drastic layering change and inthe density flowability was observedwas also enhanced. at >10% concentration These prepared in the granules polymer tended granules. to become The granule denser with particle SGR size, and size a drastic distribution, change andin density particle was configuration observed at can >10% be concentration controlled by thein the concentration polymer granules. of the polymericThe granule binder particle and size, the processingsize distribution, time of and SGR. particle configuration can be controlled by the concentration of the polymeric binder and the processing time of SGR.

FigureFigure 3.3. SEMSEM imagesimages ofof thethe 00−−30% PVP-VA granulesgranules atat thethe samesame magniﬁcationmagnification ( ×(×500).500). The scale barbar indicatesindicates 5050 µμm.m.

Table 2.2. PhysicalPhysical propertiesproperties ofof SGRSGR granules.granules.

11 PVP-VAPVP-VA 2 3 3 3 4 ◦ 5 6 7 ρρBB 2 (g/cm(g/cm3) ρTρT 3(g/cm (g/cm3)) ARAR 4( (°)) HRHR 5 CI 6 (%)(%) D50 D50 7 (μ(µm)m) (%)(%) 00 0.27 0.27± ± 0.02 0.51 0.51± ± 0.030.03 43.9 43.9± ± 4.994.99 1.881.88± ± 0.02 46.9 ± 0.650.65 4.18 ± 0.030.03 55 0.33 0.33± ± 0.01 0.55 0.55± ± 0.040.04 40.3 40.3± ± 4.594.59 1.671.67± ± 0.14 40.0 ± 5.235.23 11.2 ± 0.120.12 1010 0.52 0.52± ± 0.01 0.67 0.67± ± 0.000.00 39.5 39.5± ± 3.983.98 1.291.29± ± 0.03 22.7 ± 1.761.76 44.2 ± 0.170.17 2020 0.51 0.51± ± 0.02 0.71 0.71± ± 0.010.01 36.3 36.3± ± 4.544.54 1.391.39± ± 0.05 27.8 ± 2.792.79 32.5 ± 0.210.21 3030 0.61 0.61± ± 0.00 0.76 0.76± ± 0.000.00 27.9 27.9± ± 4.164.16 1.261.26± ± 0.00 20.4 ± 0.140.14 72.7 ± 2.992.99 1 2 3 1 WeightWeight parentage parentage of polyvinylpyrrolidone/vinyl of polyvinylpyrrolidone/ acetatevinyl copolymeracetate copolymer in the granule, in thebulk granule, density, 2 bulktapped density, density, 3 4 angle of repose, 5 Hausner ratio, 6 Carr index, 7 mass median diameter. tapped density, 4 angle of repose, 5 Hausner ratio, 6 Carr index, 7 mass median diameter. 3.2. Stability of Amorphous Solid Dispersion 3.2. Stability of Amorphous Solid Dispersion In efforts to gain an insight into the crystallization properties, amorphous state stability testing In efforts to gain an insight into the crystallization properties, amorphous state stability testing was performed in conditions of high and low humidity and the thermal analysis investigated the was performed in conditions of high and low humidity and the thermal analysis investigated the thermodynamic and phase behavior. The SGR granules had been conﬁrmed to have no moisture thermodynamic and phase behavior. The SGR granules had been confirmed to have no moisture content, such as free and crystal water, by thermal analysis, then the stability testing was carried content, such as free and crystal water, by thermal analysis, then the stability testing was carried out. out. Figures4 and5 show the compiled XRD patterns of storage at the conditions of 20 ◦C/30% Figures 4 and 5 show the compiled XRD patterns of storage at the conditions of 20 °C/30% RH and RH and 20 ◦C/75% RH, respectively. Each XRD pattern on the ﬁrst day (0 day) was a diffraction 20 °C/75% RH, respectively. Each XRD pattern on the first day (0 day) was a diffraction halo, halo, indicating RBM in granule was an amorphous state in the polymeric matrix by SGR, despite the indicating RBM in granule was an amorphous state in the polymeric matrix by SGR, despite the various PVP-VA concentrations. The amorphous state was maintained for 6 months at 20 ◦C/30% RH. various PVP-VA concentrations. The amorphous state was maintained for 6 months at 20 °C/30% RH. Under the high relative humidity conditions (20 ◦C/75% RH), stability was improved depending on Under the high relative humidity conditions (20 °C/75% RH), stability was improved depending on the concentration of PVP-VA. The samples with 0%, 5%, 10%, 20%, and 30% PVP-VA crystallized after the concentration of PVP-VA. The samples with 0%, 5%, 10%, 20%, and 30% PVP-VA crystallized 4, 7, 11, and 15 days. Relatively stable ASD granules could be prepared with a high concentration of after 4, 7, 11, and 15 days. Relatively stable ASD granules could be prepared with a high concentration of PVP-VA. According to Hancock [36], the glass transition temperature of polymer decreases with the increase in water content in the polymer matrix. Hence, the glass transition temperature of amorphous RBM may become lower and the amorphous state is destabilized due to compositing with the polymer. However, the stability of the amorphous state was improved with increasing the

Pharmaceutics 2019, 11, 159 7 of 13

PVP-VA. According to Hancock [36], the glass transition temperature of polymer decreases with the increase in water content in the polymer matrix. Hence, the glass transition temperature of amorphous

RBMPharmaceutics may become 2019, 11 lowerFOR PEER and REVIEW the amorphous state is destabilized due to compositing with the polymer.7 However,Pharmaceutics the 2019 stability, 11 FOR PEER of the REVIEW amorphous state was improved with increasing the polymer content.7 Itpolymer suggests content. that the It interaction suggests that between the interaction RBM and between PVP-VA RBM restricts and crystallizationPVP-VA restricts of RBM. crystallization Notably, polymer content. It suggests that the interaction between RBM and PVP-VA restricts crystallization theof RBM. diffraction Notably, peaks the ofdiffraction granules, peaks after of crystallization, granules, after was crystallization, different from was RBM, different as is.from There RBM, is as a of RBM. Notably, the diffraction peaks of granules, after crystallization, was different from RBM, as possibilityis. There is that a possibility REB formed that co-amorphously REB formed co-amorp with sodiumhously ions with in thesodium SGR granuleions in the and SGR a sodium granule salt and of is. There is a possibility that REB formed co-amorphously with sodium ions in the SGR granule and RBMa sodium was formedsalt of RBM or crystallized was formed by or absorption crystallized of moisture. by absorption The interaction of moisture. between The interaction RBM and between sodium a sodium salt of RBM was formed or crystallized by absorption of moisture. The interaction between ionsRBM is and discussed sodium in ions FT-IR is discussed analysis part. in FT-IR analysis part. RBM and sodium ions is discussed in FT-IR analysis part.

FigureFigure 4.4. XRDXRD patternspatterns ofof SGRSGR granulesgranules afterafter storagestorage atat 20 20◦ C/30%°C/30% RH.RH. PercentagesPercentages indicateindicate thethe Figure 4. XRD patterns of SGR granules after storage at 20 °C/30% RH. Percentages indicate the weightweight percentage percentage of of PVP-VA PVP-VA in in the the granules. granules. weight percentage of PVP-VA in the granules.

Figure 5. XRD patterns of SGR granules after storage at 20 ◦C/75% RH. Percentages indicate the Figure 5. XRD patterns of SGR granules after storage at 20 °C/75% RH. Percentages indicate the weightFigure percentage5. XRD patterns of PVP-VA of SGR in thegranules granules. after storage at 20 °C/75% RH. Percentages indicate the weight percentage of PVP-VA in the granules. weight percentage of PVP-VA in the granules. Figure6 shows DSC curves of the SGR granules. Each granule had a baseline shift, according Figure 6 shows DSC curves of the SGR granules. Each granule had a baseline shift, according to to theFigure glass 6 transition, shows DSC at curves approximately of the SGR 200.0 granules.◦C and Each the granule crystallization had a baseline temperatures shift, according of 0%, 5%, to the glass transition, at approximately 200.0 °C and the crystallization temperatures of 0%, 5%, 10%, 10%,the glass 20%, transition, and 30% at PVP-VA approximately granules 200.0 were °C 263.9 and ◦theC, crystallization 263.5 ◦C, 258.6 temperatures◦C, 255.7 ◦C, of and 0%, 246.75%, 10%,◦C, 20%, and 30% PVP-VA granules were 263.9 °C, 263.5 °C, 258.6 °C, 255.7 °C, and 246.7 °C, respectively. respectively.20%, and 30% Hence, PVP-VA it was granules confirmed were that263.9 the °C, samples 263.5 °C, were 258.6 established °C, 255.7 °C, as ASDand 246.7 granules. °C, respectively. To analyze Hence, it was confirmed that the samples were established as ASD granules. To analyze the glass theHence, glass it transitionwas confirmed in detail, that modulated the samples DSC were was es employed,tablished as and ASD the granules. results are To shownanalyze in the Table glass3. transition in detail, modulated DSC was employed, and the results are shown in Table 3. Glass Glasstransition transition in detail, temperature modulated is well-known DSC wasas employed an important, and value the ofresults ASD. are The shown observed in glassTable transition 3. Glass transition temperature is well-known as an important value of ASD. The observed glass transition of oftransition the 0% PVP-VAtemperature granule is well-known (amorphous as RBM)an important was 215.4 value◦C, of while ASD.unprocessed The observed pure glass PVP-VA transition was of the 0% PVP-VA granule (amorphous RBM) was 215.4 °C, while unprocessed pure PVP-VA was 107.8 107.8the 0%◦C, PVP-VA which meantgranule amorphous (amorphous RBM RBM) originally was 215.4 has °C, a while high thermodynamic unprocessed pure stability. PVP-VA The was reason 107.8 °C, which meant amorphous RBM originally has a high thermodynamic stability. The reason why why°C, which the glass meant transition amorphous temperature RBM originally decreased has with a high increasing thermodynamic concentrations stability. of the The polymer reason waswhy the glass transition temperature decreased with increasing concentrations of the polymer was due to duethe glass to the transition addition oftemperature PVP-VA to decreased the formulation. with incr Furthermore,easing concentrations the value ofof ∆theTg polymerrepresent was a specific due to the addition of PVP-VA to the formulation. Furthermore, the value of ΔTg represent a specific interactionthe addition between of PVP-VA the API to andthe form the polymericulation. Furthermore, carrier, because the value the positive of ΔTg deviation represent reflects a specific an interaction between the API and the polymeric carrier, because the positive deviation reflects an interaction between the API and the polymeric carrier, because the positive deviation reflects an increase in interactions. The deviation appeared when the number and strength of interactions increase in interactions. The deviation appeared when the number and strength of interactions between homo-materials were lower than between hetero-materials [35–37]. The calculated value between homo-materials were lower than between hetero-materials [35–37]. The calculated value showed that SGR granules with PVP-VA have interactions that lead to time scale stabilization, as showed that SGR granules with PVP-VA have interactions that lead to time scale stabilization, as with the results of XRD. The strength increased with the PVP-VA concentration. On the other hand, with the results of XRD. The strength increased with the PVP-VA concentration. On the other hand, the 0% PVP-VA granule interaction was low because of the absence of the polymer. These results of the 0% PVP-VA granule interaction was low because of the absence of the polymer. These results of XRD and DSC demonstrated that the thermodynamic stability of the ASD granules by SGR was XRD and DSC demonstrated that the thermodynamic stability of the ASD granules by SGR was

Pharmaceutics 2019, 11, 159 8 of 13 increase in interactions. The deviation appeared when the number and strength of interactions between homo-materials were lower than between hetero-materials [35–37]. The calculated value showed that SGR granules with PVP-VA have interactions that lead to time scale stabilization, as with the results of XRD. The strength increased with the PVP-VA concentration. On the other hand, the 0% PVP-VA granule interaction was low because of the absence of the polymer. These results of XRD and PharmaceuticsDSC demonstrated 2019, 11 FOR that PEER the REVIEW thermodynamic stability of the ASD granules by SGR was sufﬁciently high8 because the glass transition was over 178.7 ◦C and also, even pure PVP-VA was high enough (107.8 ◦C), sufficiently high because the glass transition was over 178.7 °C and also, even pure PVP-VA was high whereas undesirable crystallization was provoked under the high humidity condition (20 ◦C/75% enough (107.8 °C), whereas undesirable crystallization was provoked under the high humidity RH). The effect of humidity on the crystallization can be prevented by using a high concentration of condition (20 °C/75% RH). The effect of humidity on the crystallization can be prevented by using a polymer or granule coating [38,39]. high concentration of polymer or granule coating [38,39].

Figure 6. Total heat ﬂow curves of RBM crystals and SGR granules with 0−30% PVP-VA by DSC. Figure 6. Total heat flow curves of RBM crystals and SGR granules with 0−30% PVP-VA by DSC.

Table 3. Measured and calculated glass transition temperatures of SGR granules. Table 3. Measured and calculated glass transition temperatures of SGR granules.

1 2 2 3 3 PVP-VA PVP-VA TTgg expt expt Tg calc Tg calc ∆Tg ΔTg ◦ ◦ ◦ (%) (%) ((°C)C) ( C) (°C) ( C) (°C) 0 0 215.4 215.4 n/a n/a n/a n/a 5 5 206.9 206.9 202.0 202.0 4.9 4.9 10 10 203.9 203.9 194.3 194.3 9.6 9.6 20 191.7 175.0 16.7 20 191.7 175.0 16.7 30 178.7 157.5 21.2 30 178.7 157.5 21.2 1 g 2 g 3 g g T1 experimental, 2T calculated, 3 T experimental − T calculated. Tg experimental, Tg calculated, Tg experimental − Tg calculated. 3.3. Molecular State 3.3. Molecular State SGR granules have intermolecular interactions between the API and PVP-VA in proportion to SGR granules have intermolecular interactions between the API and PVP-VA in proportion to the polymer concentration, as described in the preceding section. This section explains in detail the the polymer concentration, as described in the preceding section. This section explains in detail molecular state change of the granules, according to the interaction. Figure 7A shows the IR spectra the molecular state change of the granules, according to the interaction. Figure7A shows the IR of ASD granules by SGR. Bulk RBM crystals had an absorption peak at 1735 cm−1, due to the C12=O13 spectra of ASD granules by SGR. Bulk RBM crystals had an absorption peak at 1735 cm−1, due to the stretching vibration. However, this peak disappeared after the SGR process and different peaks at C12=O13 stretching vibration. However, this peak disappeared after the SGR process and different 1595 cm−1 and 1394 cm−1, which correspond to COO− asymmetric and symmetric stretching vibrations, peaks at 1595 cm−1 and 1394 cm−1, which correspond to COO− asymmetric and symmetric stretching appeared. These indicated that ionization had occurred due to deprotonation at the carboxy group. vibrations, appeared. These indicated that ionization had occurred due to deprotonation at the carboxy Hence, the carboxylate COO− group is suggested to exist without ionic interaction with sodium ions. group. Hence, the carboxylate COO− group is suggested to exist without ionic interaction with sodium The characteristic peak of RBM crystals at 1645 cm−1, which was assigned to the amide I band of ions. The characteristic peak of RBM crystals at 1645 cm−1, which was assigned to the amide I band of C8=O9 and C18=O19, disappeared in the granules. Bulk PVP-VA peaks of C=O stretching vibration C8=O9 and C18=O19, disappeared in the granules. Bulk PVP-VA peaks of C=O stretching vibration in in ester and the amide I band were 1724 cm−1 and 1655 cm-1, respectively. The other peaks of the amide II and III bands were weak, as shown in Figure 7A. To detect some weak peaks, second derivative spectra of the SGR granules were calculated (Figure 7B). The second derivative preprocessing allows more specific identification of weak peaks in the original spectra and offers the cancelling of baseline shift [40]. The positive value of the original data was converted into a strong negative peak using the second derivative. The characteristic peaks of RBM at 1480 cm−1, 1510 cm−1, and 1540 cm−1 indicated C8-N10 coupled with N10-H and C18-N20 coupled with N20–H vibrations (amide II band). These bands, which were based on amides, appeared strongly in granules, because the interaction between molecules of RBMs may be weakened by the

Pharmaceutics 2019, 11 FOR PEER REVIEW 9 Pharmaceutics 2019, 11, 159 9 of 13 amorphization process. These bands were also shifted or disappeared in proportion to the PVP-VA concentration, the amide of RBM interacts with the matrix though hydrogen bonding. Therefore, the −1 −1 esterinteraction and the between amide IRBM band and were PVP-VA 1724 cm wasand present 1655 in cm SGR, respectively.granules. The The indication other peaks corresponded of the amide to II and III bands were weak, as shown in Figure7A. the result of ΔTg analysis, shown in Table 3.

Figure 7. (A) Overlays of IR spectra of RBM crystals alone, PVP-VA alone, and SGR granules including Figure 7. (A) Overlays of IR spectra of RBM crystals alone, PVP-VA alone, and SGR granules 0−30% PVP-VA. (B) Representation of the second derivatives of SGR granules. including 0−30% PVP-VA. (B) Representation of the second derivatives of SGR granules. To detect some weak peaks, second derivative spectra of the SGR granules were calculated 3.4. Dissolution Ability (Figure7B). The second derivative preprocessing allows more specific identification of weak peaks in the originalFigure spectra8A shows and the offers dissolution the cancelling profiles of baselineof the tablets shift [40in]. water. The positive All tablets, value including of the original SGR datagranules, was convertedshowed enhanced into a strong solubility negative of the peak RBM using crystals the second and the derivative. dissolved The concentration characteristic reached peaks ofalmost RBM 100% at 1480 (126.67 cm−1, 1510μg/mL) cm −at1, and120 1540min, cmwhereas−1 indicated RBM C8-N10crystals coupleddissolved with slowly. N10-H In and Figure C18-N20 8B, coupleddissolution with testing N20–H using vibrations an acidic (amide medium II band). was pe Theserformed bands, with which dispersible were based SGR on granules, amides, due appeared to the stronglylow solubility in granules, of weakly because acidic the RBM. interaction The dissolution between moleculesprofiles in ofthe RBMs acidic may solution be weakened were different by the amorphizationcompared with process.in water. TheseAll of bandsthe SGR were granules also shifted were more or disappeared soluble than in RBM proportion crystals; to however, the PVP-VA the concentration,profiles depended the amideon the ofconcentration RBM interacts of PVP-VA with the in matrix the granules. though hydrogenIn low PVP-VA bonding. formulations, Therefore, thesuch interaction as 0% and between 5%, the RBMdissolved and PVP-VA concentration was present reached in SGRapproximately granules. The 2.22 indication μg/mL. Granules corresponded with to10% the PVP-VA result of reached∆Tg analysis, the highest shown solubility in Table3 (11.89. μg/mL) among the samples shown in Figure 8B, which was about 10 times higher than RBM crystals. In granules, including 20% and 30% PVP-VA, 3.4.gelation Dissolution was observed Ability and the dissolved amount of RBM, at 120 min, decreased with increasing concentrationFigure8A of shows the polymer. the dissolution Generally, profiles the recrys of thetallization tablets inand water. crystal All growth tablets, were including prevented SGR by granules,the interaction showed with enhanced the polymer; solubility thus, of the the polymer RBM crystals contributes and the to dissolvedfurther improvement concentration of reachedthe API almostsolubility 100% [41,42]. (126.67 However,µg/mL) the at wettability 120 min, whereasand swel RBMlability crystals of granules dissolved were slowly. in proportion In Figure to 8theB, dissolutionconcentration testing of polymer, using anwhile acidic the mediumdispersibility was performedof granules withwas decreased. dispersible Higher SGR granules, the content due rate to theof the low polymer solubility caused of weakly aggregation acidic RBM. and Thegelation dissolution in the vessel, profiles consequently in the acidic solutionleading to were lower different drug comparedrelease from with granules in water. in this All study. of the It SGR should granules be noted were that more the solubledissolution than profile RBM crystals;may change however, if the theamount profiles of contents depended was on revised. the concentration Optimized of formul PVP-VAation in ratios, the granules. depending In low on PVP-VArespective formulations, objectives, suchare vital as 0%for andthe pharmaceutical 5%, the dissolved industry. concentration reached approximately 2.22 µg/mL. Granules with 10% PVP-VAThe drug reached release kinetics the highest from solubility ASDs were (11.89 explµainedg/mL) based among on themathematical samples shown modeling in Figure analysis8B, which[43–45]. was As aboutthe result 10 times of an higher R2 analysis than RBM of least-squares crystals. In granules,fitting, the including best-fitted 20% was and the 30% Korsmeyer PVP-VA,− gelationPeppas model. was observed The model and is thegenerally dissolved resumed amount to the of following RBM, at 120 expression: min, decreased with increasing concentration of the polymer. Generally, the recrystallization and crystal growth were prevented by = (5) the interaction with the polymer; thus, the polymer contributes to further improvement of the API solubility [41,42]. However, the wettability and swellability of granules were in proportion to the where / is the amount of drug released on time per unit area, is the kinetics constant, concentration of polymer, while the dispersibility of granules was decreased. Higher the content rate and is the release exponent [43,44]. Each R2 value of the RBM crystal and the granules including 0 of the polymer caused aggregation and gelation in the vessel, consequently leading to lower drug −30% PVP-VA in acidic medium was 0.917, 0.989, 0.996, 0.987, 0.930, and 0.997. Additionally, each release from granules in this study. It should be noted that the dissolution profile may change if the exponent value was 1.16, 0.64, 0.34, 0.31, 0.26, and 0.38, respectively. The exponents indicate the amount of contents was revised. Optimized formulation ratios, depending on respective objectives, diffusional drug release mechanism from a matrix, < 0.43, 0.43 < < 0.85, and 0.85 < describes are vital for the pharmaceutical industry. Fickian diffusion, anomalous (non-Fickian) transport, and super case II transport, respectively

Pharmaceutics 2019, 11 FOR PEER REVIEW 10

[43,44]. These results suggested the release mechanisms of the enclosed REB, during the dissolution, were changed into Fickian diffusion due to forming ASD by PVP-VA. The release kinetics from the tabletPharmaceutics in water2019, 11was, 159 also explained by the Korsmeyer −Peppas model. Hence, the drug release10 of 13 mechanism after the disintegration of the tablet was the same as the granule.

Figure 8. Integrated dissolution profiles in 900 mL of (A) tablets in water and (B) granules in an acidic Figure 8. Integrated dissolution profiles in 900 mL of (A) tablets in water and (B) granules in an acidic solution of RBM crystal (dark triangles), PVP-VA 0% (blue circles), PVP-VA 5% (light blue crosses), solution of RBM crystal (dark triangles), PVP-VA 0% (blue circles), PVP-VA 5% (light blue crosses), PVP-VA 10% (green diamonds), PVP-VA 20% (light red rectangles), and PVP-VA 30% (red inversed PVP-VA 10% (green diamonds), PVP-VA 20% (light red rectangles), and PVP-VA 30% (red inversed triangles). Percentages denote the concentration of PVP-VA in the SGR granules. triangles). Percentages denote the concentration of PVP-VA in the SGR granules. The drug release kinetics from ASDs were explained based on mathematical modeling analysis [43–45]. 4.As Conclusions the result of an R2 analysis of least-squares fitting, the best-fitted was the Korsmeyer−Peppas model.One-step The model granulation is generally methods resumed such to as the CTS-SGR following could expression: be used to prepare ASD granules with high RBM loading to enhance the solubility of this BCS class IV drug. This method involves no Mt specific preparation and produces the ASD granul= ktesn using a continuous spraying and layering(5) M∞ system. According to the concentration of PVP-VA, the obtained granules were found to be heavy andwhere dense,Mt/ withM∞ is a thesmooth amount surface. of drug The released thermodynamic on time t stabilityper unit of area, SGRk isgranules the kinetics was constant,relatively and highn andis the the release humidity exponent stability [43 ,at44 ].20 Each °C/75%R2 value RH depen of theded RBM on crystalthe concentration and the granules of PVP-VA. including Molecular 0−30% interactionsPVP-VA in acidic formed medium between was RBM 0.917, and 0.989, PVP-VA, 0.996, 0.987, including 0.930, andthe 0.997.carboxy Additionally, group of RBM each exponentbecomingn ionizedvalue was in 1.16,SGR 0.64,granules. 0.34, 0.31,Dissolution 0.26, and testing 0.38, respectively. demonstrated The the exponents improved indicate water thesolubility diffusional of RBM, drug evenrelease in mechanismacidic media from due a to matrix, the formationn < 0.43, of 0.43 an < ASD.n < 0.85, The andSGR 0.85 method, < n describes which directly Fickian generates diffusion, granulesanomalous from (non-Fickian) solutions, transport,has the andpossibility super caseto reduce II transport, manufacturing respectively operations. [43,44]. These The results SGR methodologysuggested the can release contribute mechanisms to new ofprocess the enclosed development REB, duringin the pharmaceutical the dissolution, industry. were changed into Fickian diffusion due to forming ASD by PVP-VA. The release kinetics from the tablet in water Authorwas also Contributions: explained by The the author’s Korsmeyer contributions−Peppas are model. as follows: Hence, R.T., the Y.Ha., drug Y.Ho., release and mechanism H.K. prepared after and the analyzeddisintegration the ASD of granules; the tablet R.T. was wrote the samethe draft as the of the granule. manuscript; Y. Ha. edited and refined the manuscript; T.N. and M.O. supervised the research project. All the authors designed the protocol of the study and critically reviewed4. Conclusions and approved the final version of the manuscript. Funding:One-step The work granulation was partially methods supported such by as a CTS-SGRJSPS Overseas could Challenge be used Program to prepare for Young ASD granules Researchers, with a Young Researcher Scholarship from Hosokawa Powder Technology Foundation, and a PSJ Nagai Memorial high RBM loading to enhance the solubility of this BCS class IV drug. This method involves no Research Scholarship. specific preparation and produces the ASD granules using a continuous spraying and layering system. Acknowledgments:According to the concentration We profoundly of thank PVP-VA, Ohara the Pharmaceutical, obtained granules Fuji Chemical werefound Industry, to beand heavy BASF for and the dense, gifts ® ® ofwith rebamipide, a smooth Neusilin surface. NS2N, The thermodynamicand Kollidon VA64, stability respectively. of SGR Spectris granules kind wasly supported relatively the high particle and size the distribution measurement using Mastersizer 3000E. We thank Raj Suryanarayanan and Naga Kiran Duggirala humidity stability at 20 ◦C/75% RH depended on the concentration of PVP-VA. Molecular interactions fruitful discussions. formed between RBM and PVP-VA, including the carboxy group of RBM becoming ionized in SGR Conflictsgranules. of Dissolution Interest: The testing authors demonstrated declare that they the improvedhave no competing water solubility interests. of RBM, even in acidic media due to the formation of an ASD. The SGR method, which directly generates granules from solutions, Referenceshas the possibility to reduce manufacturing operations. The SGR methodology can contribute to new process development in the pharmaceutical industry.

Pharmaceutics 2019, 11, 159 11 of 13

Author Contributions: The author’s contributions are as follows: R.T., Y.H. (Yusuke Hattori), Y.H. (Yukun Horie), and H.K. prepared and analyzed the ASD granules; R.T. wrote the draft of the manuscript; Y.H. (Yusuke Hattori) edited and refined the manuscript; T.N. and M.O. supervised the research project. All the authors designed the protocol of the study and critically reviewed and approved the final version of the manuscript. Funding: The work was partially supported by a JSPS Overseas Challenge Program for Young Researchers, a Young Researcher Scholarship from Hosokawa Powder Technology Foundation, and a PSJ Nagai Memorial Research Scholarship. Acknowledgments: We profoundly thank Ohara Pharmaceutical, Fuji Chemical Industry, and BASF for the gifts of rebamipide, Neusilin® NS2N, and Kollidon® VA64, respectively. Spectris kindly supported the particle size distribution measurement using Mastersizer 3000E. We thank Raj Suryanarayanan and Naga Kiran Duggirala fruitful discussions. Conflicts of Interest: The authors declare that they have no competing interests.

References

1. Ku, M.S.; Dulin, W. A biopharmaceutical classification-based Right-First-Time formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept. Pharm. Dev. Technol. 2012, 17, 285–302. [CrossRef][PubMed] 2. Amidon, G.L.; Lennernäs, H.; Shah, V.P.; Crison, J.R. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability. Pharm. Res. 1995, 12, 413–420. [CrossRef] 3. Kawakami, K. Modification of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving bioavailability of poorly absorbed drugs. Adv. Drug Deliv. Rev. 2012, 64, 480–495. [CrossRef] 4. Perrut, M.; Jung, J.; Leboeuf, F. Enhancement of dissolution rate of poorly-soluble active ingredients by supercritical fluid processes: Part I: Micronization of neat particles. Int. J. Pharm. 2005, 288, 3–10. [CrossRef] 5. Alonzo, D.E.; Zhang, G.G.Z.; Zhou, D.; Gao, Y.; Taylor, L.S. Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution. Pharm. Res. 2010, 27, 608–618. [CrossRef][PubMed] 6. Liversidge, G.G.; Cundy, K.C. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int. J. Pharm. 1995, 125, 91–97. [CrossRef] 7. Aitipamula, S.; Banerjee, R.; Bansal, A.K.; Biradha, K.; Cheney, M.L.; Choudhury, A.R.; Desiraju, G.R.; Dikundwar, A.G.; Dubey, R.; Duggirala, N.; et al. Polymorphs, Salts, and Cocrystals: What’s in a Name? Cryst. Growth Des. 2012, 12, 2147–2152. [CrossRef] 8. Pitha, J.; Milecki, J.; Fales, H.; Pannell, L.; Uekama, K. Hydroxypropyl-β-cyclodextrin: Preparation and characterization; effects on solubility of drugs. Int. J. Pharm. 1986, 29, 73–82. [CrossRef] 9. Chiou, W.L.; Riegelman, S. Pharmaceutical Applications of Solid Dispersion Systems. J. Pharm. Sci. 1971, 60, 1281–1302. [CrossRef] 10. Serajuddin, A.T.M. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 1999, 88, 1058–1066. [CrossRef] 11. Karagianni, A.; Kachrimanis, K.; Nikolakakis, I. Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery. Pharmaceutics 2018, 10, 98. [CrossRef][PubMed] 12. Fung, M.H.; Suryanarayanan, R. Effect of Organic Acids on Molecular Mobility, Physical Stability, and Dissolution of Ternary Ketoconazole Spray-Dried Dispersions. Mol. Pharm. 2019, 16, 41–48. [CrossRef] 13. Yu, L. Amorphous pharmaceutical solids: Preparation, characterization and stabilization. Adv. Drug Deliv. Rev. 2001, 48, 27–42. [CrossRef] 14. Fung, M.H.; DeVault, M.; Kuwata, K.T.; Suryanarayanan, R. Drug-Excipient Interactions: Effect on Molecular Mobility and Physical Stability of Ketoconazole–Organic Acid Coamorphous Systems. Mol. Pharm. 2018, 15, 1052–1061. [CrossRef][PubMed] 15. Frank, D.S.; Matzger, A.J. Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality. Mol. Pharm. 2018, 15, 2714–2720. [CrossRef] Pharmaceutics 2019, 11, 159 12 of 13

16. Agrawal, A.M.; Dudhedia, M.S.; Zimny, E. Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale. AAPS PharmSciTech 2016, 17, 133–147. [CrossRef][PubMed] 17. Kaur, P.; Singh, S.K.; Garg, V.; Gulati, M.; Vaidya, Y. Optimization of spray drying process for formulation of solid dispersion containing polypeptide-k powder through quality by design approach. Powder Technol. 2015, 284, 1–11. [CrossRef] 18. Chen, J.; Ormes, J.D.; Higgins, J.D.; Taylor, L.S. Impact of Surfactants on the Crystallization of Aqueous Suspensions of Celecoxib Amorphous Solid Dispersion Spray Dried Particles. Mol. Pharm. 2015, 12, 533–541. [CrossRef] 19. Wilson, V.; Lou, X.; Osterling, D.J.; Stolarik, D.F.; Jenkins, G.; Gao, W.; Zhang, G.G.Z.; Taylor, L.S. Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: Phase behavior during dissolution, speciation, and membrane mass transport. J. Control. Release 2018, 292, 172–182. [CrossRef] 20. Nie, H.; Xu, W.; Taylor, L.S.; Marsac, P.J.; Byrn, S.R. Crystalline solid dispersion-a strategy to slowdown salt disproportionation in solid state formulations during storage and wet granulation. Int. J. Pharm. 2017, 517, 203–215. [CrossRef] 21. Sekiguchi, K.; Obi, N. Studies on Absorption of Eutectic Mixture. I. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man. Chem. Pharm. Bull. 1961, 9, 866–872. [CrossRef] 22. Patil, H.; Tiwari, R.V.; Repka, M.A. Hot-Melt Extrusion: From Theory to Application in Pharmaceutical Formulation. AAPS PharmSciTech 2016, 17, 20–42. [CrossRef] 23. Mayersohn, M.; Gibaldi, M. New Method of Solid-State Dispersion for Increasing Dissolution Rates. J. Pharm. Sci. 1966, 55, 1323–1324. [CrossRef][PubMed] 24. Takeuchi, H.; Nagira, S.; Yamamoto, H.; Kawashima, Y. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. Int. J. Pharm. 2005, 293, 155–164. [CrossRef] 25. Konno, H.; Taylor, L.S. Influence of Different Polymers on the Crystallization Tendency of Molecularly Dispersed Amorphous Felodipine. J. Pharm. Sci. 2006, 95, 2692–2705. [CrossRef] 26. Konno, H.; Handa, T.; Alonzo, D.E.; Taylor, L.S. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm. 2008, 70, 493–499. [CrossRef] 27. Yajima, T.; Nogata, A.; Demachi, M.; Umeki, N.; Itai, S.; Yunoki, N.; Nemoto, M. Particle Design for Taste-Masking Using a Spray-Congealing Technique. Chem. Pharm. Bull. 1996, 44, 187–191. [CrossRef] 28. Burggraeve, A.; Monteyne, T.; Vervaet, C.; Remon, J.P.; Beer, T. De Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: A review. Eur. J. Pharm. Biopharm. 2013, 83, 2–15. [CrossRef] 29. Elversson, J.; Millqvist-Fureby, A.; Alderborn, G.; Elofsson, U. Droplet and Particle Size Relationship and Shell Thickness of Inhalable Lactose Particles During Spray Drying. J. Pharm. Sci. 2003, 92, 900–910. [CrossRef] 30. Kimura, S.; Uchida, S.; Kanada, K.; Namiki, N. Effect of granule properties on rough mouth feel and palatability of orally disintegrating tablets. Int. J. Pharm. 2015, 484, 156–162. [CrossRef][PubMed] 31. Naito, Y.; Yoshikawa, T. Rebamipide: A gastrointestinal protective drug with pleiotropic activities. Expert Rev. Gastroenterol. Hepatol. 2010, 4, 261–270. [CrossRef][PubMed] 32. Tanaka, R.; Takahashi, N.; Nakamura, Y.; Hattori, Y.; Ashizawa, K.; Otsuka, M. Performance of an acoustically mixed pharmaceutical dry powder delivered from a novel inhaler. Int. J. Pharm. 2018, 538, 130–138. [CrossRef] 33. Hausner, H.H. Friction conditions in a mass of metal powder. Int. J. Powder Metall. 1967, 3, 7. 34. Carr, R.L. Evaluating flow properties of solids. Chem. Eng. 1965, 72, 163–168. 35. Couchman, P.R.; Karasz, F.E. A Classical Thermodynamic Discussion of the Effect of Composition on Glass-Transition Temperatures. Macromolecules 1978, 11, 117–119. [CrossRef] 36. Hancock, B.C.; Zografi, G. The Relationship Between the Glass Transition Temperature and the Water Content of Amorphous Pharmaceutical Solids. Pharm. Res. 1994, 11, 471–477. [CrossRef][PubMed] 37. Song, Y.; Yang, X.; Chen, X.; Nie, H.; Byrn, S.; Lubach, J.W. Investigation of Drug–Excipient Interactions in Lapatinib Amorphous Solid Dispersions Using Solid-State NMR Spectroscopy. Mol. Pharm. 2015, 12, 857–866. [CrossRef] Pharmaceutics 2019, 11, 159 13 of 13

38. Petereit, H.-U.; Weisbrod, W. Formulation and process considerations affecting the stability of solid dosage forms formulated with methacrylate copolymers. Eur. J. Pharm. Biopharm. 1999, 47, 15–25. [CrossRef] 39. Wu, T.; Sun, Y.; Li, N.; de Villiers, M.M.; Yu, L. Inhibiting Surface Crystallization of Amorphous Indomethacin by Nanocoating. Langmuir 2007, 23, 5148–5153. [CrossRef][PubMed] 40. Buckton, G.; Yonemochi, E.; Hammond, J.; Moffat, A. The use of near infra-red spectroscopy to detect changes in the form of amorphous and crystalline lactose. Int. J. Pharm. 1998, 168, 231–241. [CrossRef] 41. Simonelli, A.P.; Mehta, S.C.; Higuchi, W.I. Dissolution rates of high energy sulfathiazole-povidone coprecipitates II: Characterization of form of drug controlling its dissolution rate via solubility studies. J. Pharm. Sci. 1976, 65, 355–361. [CrossRef][PubMed] 42. Gupta, P.; Kakumanu, V.K.; Bansal, A.K. Stability and Solubility of Celecoxib-PVP Amorphous Dispersions: A Molecular Perspective. Pharm. Res. 2004, 21, 1762–1769. [CrossRef][PubMed] 43. Ritger, P.L.; Peppas, N.A. A simple equation for description of solute release I. Fickian and non-ﬁckian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J. Control. Release 1987, 5, 23–36. [CrossRef] 44. Ritger, P.L.; Peppas, N.A. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J. Control. Release 1987, 5, 37–42. [CrossRef] 45. Mehanna, M.M.; Motawaa, A.M.; Samaha, M.W. In sight into tadalaﬁl – block copolymer binary solid dispersion: Mechanistic investigation of dissolution enhancement. Int. J. Pharm. 2010, 402, 78–88. [CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).