International Journal of Pharmaceutics 485 (2015) 348–356

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Co-processing of hydroxypropyl methylcellulose (HPMC) for improved aqueous dispersibility Payal Sharma, Sameer R. Modi, Arvind K. Bansal * Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 December 2014 Received in revised form 13 March 2015 Accepted 16 March 2015 Available online 18 March 2015

Hydroxypropyl methylcellulose (HPMC), a widely employed film coating polymer, exhibits poor dispersibility in an aqueous medium. Rapid hydration leading to swelling and coherent gel formation is reported to be responsible for this problem. Present study focuses on the use of spray drying based approach for co-processing of HPMC to improve its dispersibility. Dispersion behavior of native HPMC showed formation of large lumps that did not dissolve completely for 40 min. However, HPMC co-processed with lactose and sodium chloride exhibited improvement in dispersibility with complete dissolution attained within 20 min. Mechanistic insights into improved dispersibility were obtained using contact angle studies, confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM) and scanning TEM (STEM) studies. Co-processed products exhibited higher immersional wetting as determined by sessile drop contact angle technique, which indicated spontaneous incursion of water. CLSM study revealed highly swollen and erodible gel in co-processed products. Novel application of TEM and STEM techniques was developed to understand the nature of mixing achieved during co-processing. Overall the improvement in dispersibility of co-processed products was predominantly due to the alteration in sub-particulate level properties during co-processing. The effect of excipients on the film properties of HPMC, like tensile strength and hygroscopicity, was also assessed. This study provides the comprehensive understanding of role of co-processing on improvement of dispersion behavior of HPMC and helps in the selection of suitable excipients for the same. ã 2015 Elsevier B.V. All rights reserved.

Keywords: Hydroxypropyl methylcellulose (HPMC) Co-processing Dispersion Gel layer Swelling Microscopic techniques

1. Introduction Cellulose ethers are important materials that find application in numerous spheres of industry (Dow, 2012). Amongst various cellulose ethers, hydroxypropyl methylcellulose (HPMC) is used routinely as a coating for pharmaceutical tablets. This is because of its ability to coat using aqueous system that improves environmental safety (Aulton et al., 1981). However, difficulties are encountered when HPMC is dispersed into an aqueous medium (Savage, 1976). The polymer agglomerates in cold water, thus making it difficult to disperse (Nimerick and Simpson, 1977). Prolonged processing is required to fully disperse these agglomerates (Bonney and Ramaile, 2007). Various attempts have been made to improve its dispersibility. These include use of crosslinking agents (Bhargava et al., 2012; Ingvar, 1959; Majewicz, 1982;

* Corresponding author. Tel.: +91 172 2214682 87; fax: +91 172 2214692. E-mail addresses: [email protected], [email protected] (A.K. Bansal). http://dx.doi.org/10.1016/j.ijpharm.2015.03.036 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.

Reibert et al., 1997; Socha, 1983), alteration in the synthesis process (Werner, 1969), addition of excipients during synthesis of HPMC (Doengers and Hammes, 2004), adjustment of water content of fibrous ether (Maasberg and Swinehart, 1943), hydrophobic modification of HPMC by attaching different substituents (Lahteenmaki et al., 2003) and co-processing of polymer using various excipients or their combinations (Bonney and Ramaile, 2007). Coprocessing of parent excipient with another excipient allows alteration of excipient functionality by retaining the favorable attributes and supplementing with newer ones (Gupta et al., 2006; Nachaegari and Bansal, 2004; Saha and Shahiwala, 2009). Numerous patents disclose use of different excipients for co-processing of HPMC for improving its dispersion behavior. These include surfactants, salts, sugars, hydrophobic molecules and low molecular weight water soluble polymers (Alderman and Schulz, 1989; Anderson and Moeller, 1953; Bishop, 1988; Bonney and Ramaile, 2007; Bostrom and Karlsson, 2003; Cook and Sander, 1987; Hayakawa, 2008; Melbouci, 2001; Patel, 1995). The majority of information regarding use of co-processing to improve aqueous

P. Sharma et al. / International Journal of Pharmaceutics 485 (2015) 348–356

dispersibility of HPMC resides in patent literature. There is a lack of information on mechanistic understanding of effect of co-processing on dispersibility of HPMC in aqueous media. Hence, the objective of present work was to generate co-processed HPMC using spray dryer with different excipients and obtain insights on its dispersion behavior at both molecular and particulate level. Preliminary screening of co-processed products was carried out by testing dispersibility in aqueous medium. Further insights were obtained by determining work of immersion using sessile drop contact angle technique. Mechanistic evidences were generated by developing novel application of microscopic techniques like confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM) and scanning TEM (STEM), to support improved dispersibility. Further, the effect of excipients on the film forming properties of HPMC was also assessed.

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2.3. Preliminary testing of polymer aggregation behavior Preliminary testing of polymer aggregation behavior was carried out using mechanical stirrer (RQ-127A, Remi Motors, Mumbai, India), which was set at 700 revolutions per minute (rpm) and temperature of water was maintained at 25  2
C. The solid content of MethocelTM E5 in coating suspension is usually between 8-11% w/w (Pareek and Rajsharad, 2010). Hence, aggregation behavior was investigated at a concentration of 8% w/w. Silicone anti-foaming agent (0.025% w/v) was also added to reduce foaming during testing. Individual physical mixtures of HPMC with lactose and sodium chloride, prepared by geometric dilution method (desired amount of HPMC and excipient were mixed thoroughly using spatula to obtain uniform mixture), were taken as control in preliminary testing of dispersion behavior of their co-processed products.

2. Materials and methods 2.4. Preparation of pellet 2.1. Materials HPMC (MethocelTM E5 Premium LV, 28.4% methoxyl, 9.0% hydroxypropyl, BN# ZG060124L1) was received as a gift sample from the Dow Wolff Cellulosics (GmbH, Germany). The purity of the sample was mentioned to be greater than 99.0%, as per certificate of analysis provided by Dow Wolff Cellulosics. Polyethylene glycol (PEG 600), lactose and sodium chloride were obtained from S D Fine-Chem. Ltd. (Mumbai, India). Aerosil 200 and sodium lauryl sulfate (SLS) were obtained from Evonik Industries (Germany) and Sigma–Aldrich Chemie (GmbH, Germany). Silicone antifoaming agent (non-ionic) was obtained from Loba Chemie Pvt., Ltd. (Mumbai, India). All chemicals used were of analytical grade.

Rotary tablet press (Mini II, Rimek, Ahmedabad, India) was equipped at one of the 8 stations with 8 mm D-tooling with flat punch tip. Pre-compression rollers were set out of function. Pellets of each powder sample were compressed at constant volume. Pellet weight was kept at 150  5 mg and applied force was leveled by moving the pressure roller with a hand wheel. Humidity (40  5% RH) and temperature (25  2
C) conditions were monitored throughout the study. 2.4.1. Determination of pellet porosity Pellet dimensions were measured using a digital screw gauge (Digimatic Mitutoyo Corporation, Kanagawa, Japan). The porosity, e of the pellets was calculated using Eq. (1),

e¼1

2.2. Generation of co-processed products Co-processed products were prepared using laboratory scale spray dryer (U228 Model, Labultima Ltd., Mumbai, India). Aqueous polymeric solutions of 2.4% w/v concentration were prepared using “hot/cold” technique (Dow, 2002). Briefly, the desired amount of HPMC was initially dispersed by mixing thoroughly with one third of the total required volume of hot water. Mixing was continued until all particles were thoroughly wetted and dispersed. The remaining cold water was then added to facilitate complete solubilization. Five excipients were selected (Table 1) and mixed individually with polymeric solution using magnetic stirrer. These solutions were then left overnight to allow hydration of polymer. The concentration of each excipient used for co-processing has been listed in Table 1. The solutions were then spray dried at inlet temperature of 130
C, feed rate of 3.0 mL/min, air atomization pressure of 1.2 kg/cm2 and vacuum of 95–100 mm water column. Spray dried HPMC (HPMC SD) was generated and used as a control to compare dispersion behavior with co-processed products. The yield of spray dried product was about 40%. The products were stored in desiccators at 25  2
C and 0% relative humidity (RH) conditions over phosphorus pentoxide, till further use.

rc rt

(1)

where rc is the density of pellet calculated from the weight and volume of the resulting pellet. rt is the true density of powder. The true density of powder samples was determined in triplicate by helium pycnometry (Pycno 30, Smart Instruments, Mumbai, India) at 25  2
C and 40  5% RH. 2.5. Sessile drop contact angle and wetting behavior As reported earlier (Modi et al., 2014), contact angle of pellets was measured by sessile drop method using Drop Shape Analyzer instrument (FTA 1000, First Ten Angstrom, Virginia, USA) operating with FTA32 software. Pellets were mounted on glass slide and drop of probe liquid was dispensed on them. The video was captured by the FTA image analyzer. Contact angle was calculated by the instrument by fitting mathematical expression to the shape of the drop and then calculating the slope of the tangent to the drop at the liquid–solid–vapor interface line. All measurements were performed in air under ambient conditions of 25  2
C and 40  5% RH and the reported values are an average of six measurements.

Table 1 Various excipients used for co-processing. Category

Excipient

Concentration

Surfactant Hydrophobic molecules Low molecular weight polymers Sugars Salts

SLS Aerosil 200 PEG 600 Lactose Sodium chloride

6.72% based on dry polymer weight (to achieve 6 mM concentration of solution) 20% based on dry polymer weight 20% based on dry polymer weight 25% based on dry polymer weight 12.5% based on dry polymer weight

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2.7.3. Thermogravimetric analysis (TGA) Presence of solvent, moisture or any degradation during heating was confirmed using Mettler Toledo 851e TGA/SDTA (Mettler Toledo, Switzerland) operating with Stare software version Solaris 2.5.1. Accurately weighed powder samples (5–10 mg) were loaded in alumina crucible and heated at a heating rate of 10
C/min over a temperature range of 25–300
C, under nitrogen purge (50 mL/ min), to determine loss in weight. 2.7.4. Moisture content Moisture content of powder samples (200–300 mg) was determined by Karl Fischer titration (Metrohm 794 Basic Titrino, Herisau, Switzerland). Instrument was calibrated with water for the accuracy of moisture determination. 2.8. Particle level characterization

Fig. 1. Diagrammatic representation of experimental setup used for CLSM imaging studies.

2.6. Evaluation of early gel layer formation using CLSM Fig. 1 shows the diagrammatic representation of experimental setup used for imaging early gel layer formation using CLSM. The pellet was fixed on the glass slide and hydration medium was added in the cavity. This arrangement permitted viewing of hydration in radial direction. Images of developing gel layer were captured at various time intervals (5, 10, 15, 20 and 40 min) using Olympus FluoView FV1000CLSM (Melville, NY) equipped with a 10X/0.4NA objective lens. Changes in the radial dimensions of gel with time were quantified using FV10-SW software version 5.0c. 2.7. Molecular level characterization 2.7.1. Powder X-ray diffraction (PXRD) PXRD of powder samples was recorded at room temperature as per previously reported protocol (Tiwari et al., 2007), using Bruker’s D8 advance diffractometer (Bruker AXS, Karlsruhe, Germany) with Cu Ka radiation (1.54 Å), at 40 kV, 40 mA passing through nickel filter. Accurately weighed powder samples (about 300 mg) were loaded in a 25 mm poly-methyl methacrylate (PMMA) holder and gently pressed by a clean glass slide to ensure coplanarity of the powder surface with the surface of the holder. Analysis was performed in a continuous mode with a step size of 0.01
and step time of 1 s over an angular range of 3–40
2u. Obtained diffractograms were analyzed with DIFFRAC plus EVA, version 9.0 (Bruker AXS, Karlsruhe, Germany) diffraction software. 2.7.2. Differential scanning calorimetry (DSC) Conventional and modulated DSC (MDSC) experiments were conducted on a DSC Q2000 (TA Instruments, Delware, USA) equipped with a refrigerated cooling system and operating with Universal Analysis 2000 software version 4.5A. The sample cell was purged with dry nitrogen at a flow rate of 50 mL/min. Accurately weighed samples (3–5 mg) were scanned at a heating rate of 10
C/ min. Glass transition (Tg) measurements were performed by MDSC with modulation parameters of underlining heating rate of 5
C/ min, modulation amplitude of 0.265
and modulation period of 20 s in the temperature range of 25–200
C. A baseline shift in reversing heat flow signal, concomitant with a rise in reversing heat capacity was assigned as Tg. The DSC instrument was calibrated for temperature and cell constant using high purity indium standard.

2.8.1. Optical microscopy The powder samples were observed using a Leica DMLP polarized light microscope (Leica, Microsystems Wetzlar GmbH, Wetzlar, Germany) and the diameter (i.e., length along the longest axis of individual particles) of 300 particles was determined under 500 magnification. The cumulative particle size distribution curves were plotted to determine the diameters corresponding to 10, 50 and 90% of cumulative undersize particles, i.e., D10,D50 and D90. 2.8.2. Specific surface area The ‘single point based dynamic flow method’ as described in European Pharmacopoeia was employed for determination of surface area of powder samples. Specific surface area of powder samples was determined using nitrogen gas sorption (SMART SORB 91 Surface Area analyzer; Smart Instruments, Mumbai, India). The instrument was calibrated by injecting a known quantity of nitrogen. The measured parameters were then used to calculate the surface area of the sample by employing the adsorption theories of Brunauer, Emmett and Teller (BET). Accurately weighed powder samples were placed into the glass loop of the instrument and then submerged into liquid nitrogen. The quantity of the adsorbed gas was measured using thermal conductivity detector and then integrated using electronic circuit. The reported values were the average of three measurements. 2.8.3. Scanning electron microscopy (SEM) The surface morphology of powder samples was viewed under a scanning electron microscope (S-3400, Hitachi Ltd., Tokyo, Japan) operated at an excitation voltage of 25 kV. The powder samples were mounted onto a steel stage using double sided adhesive tape and sputter coated with gold using ion sputter (E-1010, Hitachi Ltd., Tokyo, Japan), before analysis. 2.8.4. Transmission electron microscopy (TEM) and scanning TEM (STEM) Powder samples were analyzed under TEM (FEI Tecnai G2 F20; FEI, Hillsboro, Oregon). Briefly, powder samples were directly mounted on the carbon coated copper grids and analyzed under TEM at 200 kV. A STEM- high-angle annular dark field (HAADF) detector was used for STEM studies. 2.9. Evaluation of film properties 2.9.1. Preparation of free films The free films were prepared from aqueous solutions of spray dried HPMC products by solvent evaporation method. The aqueous film coating solutions (8% w/w) were prepared by mechanical stirring at 25  2
C and plasticized with 20% w/w (based on dry

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polymer weight) PEG 600. The solutions were allowed to stand still for some time to remove entrapped air. These were then spread on a glass surface of defined area (27.5  27.5 cm2) using a laboratory coating device (model SV-M-101301, Mathis, Switzerland) followed by drying at room temperature (25  2
C and 40  5% RH) till it solidified (Aulton et al., 1981). The films were dried for at least another 24 h in a leveled oven maintained at 45  2
C before testing. Dried films were removed from the glass surface, cut into pieces of defined size (50 mm  10 mm) and stored under 0% RH at 25  2
C. Thickness of the films was measured using a digital screw gauge (Digimatic Mitutoyo Corporation, Kanagawa, Japan) and found to be within 95  5 m. 2.9.2. Tensile strength of free films The effect of excipients on the mechanical properties of HPMC films was assessed using tensile strength test. Tensile strength of free films was determined by a calibrated texture analyzer (TA-XT2i, Stable Microsystems, UK) equipped with a 50 kg load cell and rubberized tensile grips. Data was acquired at a rate of 100 points per second, using fully integrated data acquisition and analysis software (i.e., Texture Expert Version 1.22). The film was placed between tensile grips. Lower grip was fixed and the upper one was moved at a rate of 0.5 mm/s. The stress strain curve was recorded for samples and the tensile strength (force per unit crosssectional area required to break the film) was determined. The

351

reported values of tensile strength are an average of ten measurements for each sample. 2.9.3. Hygroscopicity assessment of free films The hygroscopicity data for free films was generated using the method reported by Callahan et al. (1982). Accurately weighed films (100–200 mg) were placed in open petri plates. These were then placed inside labeled desiccators containing an excess amount of saturated salt solutions of magnesium nitrate, potassium bromide and potassium nitrate to obtain % RH of 52, 83 and 93, respectively. Samples were removed after storage at 25  2
C for seven days and the moisture content was determined by Karl Fischer titration (Metrohm 794 Basic Titrino, Herisau, Switzerland). All the measurements were performed in triplicate. 3. Results 3.1. Preliminary testing of polymer aggregation behavior Powder samples were evaluated for their aqueous dispersion behavior using mechanical stirrer. It was observed that HPMC SD had very poor dispersibility in water. The particles on coming in contact with water underwent rapid hydration leading to swelling and formation of rigid gel. The presence of gel made the surface of particles sticky. This led to coalescence of particles and formation

Fig. 2. Images (top view) illustrating dispersion behavior of powder samples. The yellow arrows indicate the lumps formed. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Fig. 3. CLSM images of early gel layer formation at the boundary of hydrating pellet as a function of time. The images displayed three regions: (A) area corresponding to hydrating medium; (B) indicating swelling and gel layer formation; (C) corresponding to the dry tablet core. (‘t’ represents thickness of gel layer and the black arrow indicates direction of water penetration, respectively).

of large aggregates as shown in Fig. 2. These aggregates did not dissolve completely even after stirring for 40 min. Similarly, HPMC co-processed with SLS, Aerosil 200 and PEG 600 did not show much improvement in dispersibility and lumps were formed. On the other hand, HPMC co-processed with lactose (HPMC-LAC CP) and HPMC co-processed with sodium chloride (HPMC-NaCl CP) exhibited improvement in dispersibility with minimum lump formation. Small lumps were formed that broke immediately as depicted in Fig. 2. Almost complete polymer dissolution was observed with very few specks at the end of 20 min. To get further insights into this improved dispersibility, physical mixtures of HPMC SD with lactose (HPMC-LAC PM) and HPMC SD with sodium chloride (HPMC-NaCl PM), prepared by geometric mixing, were also evaluated for dispersion behavior. Interestingly, HPMC-LAC PM and HPMC-NaCl PM did not show any improvement in dispersibility (Refer Supporting information). This differential dispersion behavior of HPMC-LAC CP and HPMC-NaCl CP was further evaluated for immersional wetting using sessile drop contact angle technique and for gelling behavior using CLSM, as described in next section.

system during immersion. Contact angle measurements and surface tension of water were used to determine Wi and the values are 90.40 mJ/m2, 262.21 mJ/m2 and 233.16 mJ/m2 for HPMC SD, HPMC-LAC CP and HPMC-NaCl CP, respectively. Negative values of Wi obtained for these samples indicated the immersion process to be spontaneous in all the cases. However, spontaneity of immersion process was highest for HPMC-LAC CP. 3.3. Evaluation of early gel layer formation using CLSM The true density and porosity of all the prepared pellets was found to be in the range of 1.33–1.35 g/mL and 0.23–0.24, respectively. Fig. 3 shows CLSM images of the hydrating pellets undergoing swelling in radial direction. Fig. 4 shows radial swelling measurements calculated from the images. Images of HPMC SD pellet at 5 min showed rapid polymer hydration with localized areas of swelling at radial pellet edge. HPMC particles in these swollen areas solubilized and underwent coalescence to form a highly structured continuous viscous rigid gel layer. This retarded further ingress of water and the thickness of gel layer became constant with time.

HPMC SD, HPMC-LAC CP and HPMC-NaCl CP were evaluated for their wetting behavior. HPMC SD exhibited an initial contact angle of 71.97  1.56
when double distilled water was used as the probe liquid. On the other hand, HPMC-LAC CP and HPMC-NaCl CP showed an initial contact angle of 26.29  1.99
and 37.27  2.43
, respectively. The wetting process with water was quantified for the work of immersion (Wi) using Eq. (2) derived from the Young’s equation, W i ¼ 4g SL  4g LV ¼ 4g LV cosu

(2)

where u is the contact angle in degrees, g is interfacial tension and subscripts LV and SL refer to the liquid–vapor and solid–liquid interfaces, respectively (Buckton, 1988; Young and Buckton, 1990). Immersion is a process in which a solid is covered with a liquid, both of which were initially in contact with a gas, without changing the area of liquid–gas interface (Buckton, 1988; Laad et al., 2013). The work of immersion per unit area (Wi) is the work done on the

Gel layer thickness (µ)

3.2. Sessile drop contact angle and wetting behavior

500 450 400 350 300 250 200 150 100 50 0

HPMC SD

0

5

HPMC-NaCl CP

10 Time (min)

15

HPMC-LAC CP

20

40

Fig. 4. Radial swelling of the hydrating pellets in an aqueous medium. Values of gel layer thickness were obtained from the images typical of those in Fig. 3. Each value represents an average of three measurements made from the dry tablet boundary to the outermost edge of gel formation with error bars showing their standard deviations.

P. Sharma et al. / International Journal of Pharmaceutics 485 (2015) 348–356 2.8 2.6

Tg = 146.8 °C

2.2 2.0 1.8 1.6

Tg = 143.8 °C

HPMC-LAC CP

1.4 1.2 1.0 0.8

Tg = 149.2 °C

0.6

HPMC SD

0.4 0.2 0.0 -0.2

3.4. Molecular level characterization

HPMC-NaCl CP

2.4

Reversing heat flow (W/g)

Similarly, polymer swelling was also observed in both HPMCLAC CP and HPMC-NaCl CP co-processed products. However, significant differences were observed in the pattern of gel layer formation and its progressive thickness in both the co-processed products. HPMC-LAC CP showed an irregular and highly ruptured gel that exhibited erosion of polymer particles from the radial surface of pellets (Fig. 3). This contributed to the significant (p < 0.05) increase in gel layer thickness (‘B’ in Fig. 3) till 40 min (Fig. 4). On the other hand, HPMC-NaCl CP exhibited poor gel layer with very less erodible particles. It also showed increase in gel layer thickness, but this was lesser than HPMC-LAC CP. HPMC SD, HPMC-LAC CP and HPMC-NaCl CP were characterized for their molecular and particulate level properties to investigate the underlying mechanisms for these differential gel layer properties.

353

35

85

135

185

Temperature (°C)

The overlay of PXRD scans of powder samples are shown in Fig. 5. The diffractograms showed halo pattern indicating absence of crystallinity in HPMC SD and HPMC-LAC CP. HPMC-NaCl CP exhibited a characteristic diffraction peak at 2u value of 31.84
corresponding to sodium chloride. The amorphous nature of HPMC in all the samples was also confirmed by DSC heating scans where no melting endotherm was observed. Instead a broad endotherm at around 50
C was observed indicating water loss (refer Supporting information). Since Tg was not clearly seen in conventional DSC scans, MDSC analysis was carried out. The MDSC scan of all the three samples showed the onset Tg in reversing heat flow signal at around 143–150
C (Fig. 6). Presence of moisture was further confirmed by TGA and Karl Fischer titration (Table 2). 3.5. Particle level characterization The SEM microphotographs of all the spray dried powder samples i.e., HPMC SD, HPMC-LAC CP and HPMC-NaCl CP revealed particles with crenulated surfaces as depicted in Fig. 7. The D10, D50 and D90 values by optical microscopy and specific surface area were found to be similar for all the three samples (Table 3). Fig. 8 shows the images obtained under TEM. HPMC SD and HPMC-LAC CP were found to be similar at particle level whereas HPMC-NaCl CP showed the presence of particulate material entrapped in the polymeric matrix. Additionally, STEM images exhibited homogeneous nature of HPMC SD and HPMC-LAC CP

Fig. 6. Reversing signal of MDSC traces of powder samples.

samples. On the other hand, HPMC-NaCl CP showed the presence of sodium chloride crystals in the polymeric matrix (Fig. 9) that point towards heterogeneous nature of it. 3.6. Evaluation of film properties 3.6.1. Tensile strength of free films The tensile strength data showed that PEG 600 had a marked effect on decreasing the maximum tensile strength at breaking point. The tensile strength of HPMC fell from 37.20  1.87 MPa with 0% PEG 600 to 19.83  0.85 MPa with 20% PEG 600. The tensile strength of HPMC-LAC CP films was further decreased due to presence of lactose (Table 4). However, the difference was not significant (p > 0.05) when compared with the HPMC SD films. On the contrary, tensile strength of HPMC-NaCl CP films decreased significantly (p < 0.05). The tensile strength data is shown in Table 4. 3.6.2. Hygroscopicity assessment of free films Free films were evaluated for hygroscopicity behavior to understand the contribution of lactose and sodium chloride on hygroscopicity, if any. It was found that HPMC SD and HPMC-LAC CP films were ‘moderately hygroscopic’ whereas HPMC-NaCl CP films were ‘very hygroscopic’. The percentage moisture content and classification of each sample as per Callahan et al. (1982) (Murikipudi et al., 2013) has been listed in Table 4. 4. Discussion

4000

In the present investigation, spray drying based co-processing was used for the generation of co-processed HPMC. HPMC coprocessed products with lactose and sodium chloride exhibited better dispersibility over HPMC SD. Poor dispersibility of HPMC SD in cold water was consistent with the previous reports and was attributed to its rapid hydration and formation of a rigid gel layer (Alderman and Schulz, 1989; Bhargava et al., 2012; Bishop, 1988; Bonney and Ramaile, 2007; Nimerick and Simpson, 1977).

3000

Lin (Counts)

HPMC-NaCl CP

2000

HPMC-LAC CP

Table 2 Moisture content of powder samples.

1000

HPMC SD

0 3

10

20

30

2-Theta - Scale

Fig. 5. PXRD diffractograms of powder samples.

Sample

40

HPMC SD HPMC-LAC CP HPMC-NaCl CP

Moisture content (% w/w) TGA

Karl Fischer titration

3.27  1.17 2.84  0.24 2.48  0.25

3.50  0.35 2.98  0.25 2.29  0.01

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Fig. 7. SEM images of (a) HPMC SD, (b) HPMC-LAC CP and (c) HPMC-NaCl CP.

Table 3 Particle size distribution and specific surface area of powder samples. Sample

D10 (mm) D50 (mm) D90 (mm) Specific surface area (m2/g)

4.6 HPMC SD HPMC-LAC CP 4.8 HPMC-NaCl CP 4.6

6.7 6.8 6.8

8.8 9.1 9.5

6.42  0.43 6.64  0.28 6.20  0.25

The presence of lactose in HPMC-LAC CP led to the formation of a highly porous gel layer. This resulted in permeable network that allowed continuous ingress of water into the polymeric matrix. Higher work of immersion (Wi) of HPMC-LAC CP supported these observations. CLSM studies also revealed erosion of clusters of polymeric matrix that further enhances easy penetration of water molecules. HPMC-NaCl CP also exhibited slightly improved dispersibility over HPMC SD. However, in HPMC-NaCl CP, gel layer was poor (thinner) and less erodible as compared to HPMC-LAC CP. Different

Fig. 8. TEM images of (a, a1) HPMC SD; (b, b1) HPMC-LAC CP and (c, c1) HPMC-NaCl CP.

P. Sharma et al. / International Journal of Pharmaceutics 485 (2015) 348–356

355

Fig. 9. STEM images of (a, a1) HPMC SD; (b, b1) HPMC-LAC CP and (c, c1) HPMC-NaCl CP.

Table 4 Maximum tensile strength at breaking point and hygroscopicity classification of free films. Sample

Tensile strength (MPa)

HPMC SD HPMC-LAC CP HPMC-NaCl CP

19.83  0.85 18.57  0.67 15.28  0.84

a

% Moisture content at 25
C and different RH

Classificationa

52% RH

83% RH

93% RH

5.43  0.03 5.67  0.03 6.62  0.02

11.48  0.30 12.27  0.14 26.71  0.50

20.67  0.49 23.49  0.23 41.06  1.46

MH MH VH

MH: moderately hygroscopic, VH: very hygroscopic.

molecular size and dissolution kinetics of lactose and sodium chloride might have affected the gel disruption properties of the both the co-processed products. Interestingly, physical mixtures of these excipients with HPMC SD did not show any improvement in aqueous dispersibility. Hence, HPMC SD, HPMC-LAC CP and HPMC-NaCl CP were characterized for their molecular and particulate level properties to get deeper insights into the altered dispersion behavior. HPMC-LAC CP showed a single Tg at 143.8
C in DSC heating curve and halo pattern in PXRD analysis (Fig. 5). This pointed towards presence of a homogenous amorphous phase. However, it is reported that DSC is only able to differentiate domains that are above 30 nm in size (McBrierty and Packer, 2006). Calculation based on Hildebrand solubility parameters indicated miscible nature of HPMC and lactose as the difference between solubility parameter values (d) was found to be 4.1 MPa1/2. Homogeneity of HPMC and lactose in HPMC-LAC CP was further confirmed by TEM (Fig. 8) and STEM (Fig. 9) analysis that can differentiate heterogeneous domains even in sub-nanometer range (least count < 1 nm). Thus, PXRD and MDSC data along with TEM and STEM images confirmed the formation of a uniformly dispersed phase in HPMC-LAC CP. Moreover, Williams et al. have already demonstrated sugar-induced suppression of polymer hydration that restricts formation of coherent and rigid gel layer (Kabayama and Patterson, 1958; Williams et al., 2009, 2010a,b). Hence, it can be concluded that the improvement in dispersion behavior of HPMC-LAC CP was predominantly due to sub-particulate level interactions. HPMC-NaCl CP showed Tg at 146.8
C and PXRD showed characteristic peak at 2u value of 31.84
that indicated presence of crystalline sodium chloride. Absence of melting event of sodium

chloride in DSC can be attributed to its very high melting point (801
C), which was beyond the operating range of DSC. Thus, at least some sodium chloride was present in the crystalline state in HPMC-NaCl CP. TEM and STEM studies provided a clearer picture as heterogeneous domains in the nanometer range were observed (Figs. 8 and 9). Bajwa et al. (2006) had shown removal of water of hydration from methoxyl dominated domains that causes ‘saltingout’ of the polymer in the presence of ionic salts. This is because of greater affinity of ionic moieties for water molecules (Bowman et al., 2006; Liu et al., 2008; Mitchell et al., 1990; Zhang and Cremer, 2006). Thus, it can be concluded that dispersion behavior of HPMCNaCl CP was influenced by interaction at sub-particulate as well as molecular level. The film forming properties of co-processed products were also evaluated. Lactose had no significant effect on the mechanical strength of free films. On the other hand, sodium chloride significantly impaired the tensile strength of HPMC films. In addition, the hygroscopicity study revealed HPMC SD and HPMCLAC CP films as ‘moderately hygroscopic’ whereas HPMC-NaCl CP films were found to be ‘very hygroscopic’. Thus, HPMC-LAC CP provided significant improvement in aqueous dispersion behavior of HPMC. 5. Conclusions The present work emphasizes the role of co-processing in improving dispersion behavior of HPMC. HPMC was co-processed with various excipients using spray dryer. Amongst them, HPMC co-processed with lactose and sodium chloride exhibited maximum improvement in dispersibility. Sessile drop contact angle technique also provided supporting evidence by exhibiting

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improved immersional wetting of co-processed products. Further, different microscopic techniques like CLSM, TEM and STEM were employed to get deeper insights into the improved dispersion behavior and to investigate the underlying mechanisms. Improved dispersibility of co-processed products was attributed to sub-particulate and/or molecular level interactions of polymeric chains with other excipients during co-processing. This led to alteration in swelling behavior and gel forming properties of HPMC. Based on dispersion behavior, hygroscopicity and mechanical properties of polymeric films, HPMC-LAC CP was found to be a better choice. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijpharm.2015.03.036. References Alderman, D.A., Schulz, G.J., 1989. Method of Making a Granular, Cold Water Dispersible Coating Composition. The Dow Chemical Co.. Anderson, A.W., Moeller, B.V., 1953. Method of Improving the Cold-water Solubility of a Fibrous Cellulose Ether. The Dow Chemical Co.. Aulton, M.E., Abdul-Razzak, M.H., Hogan, J.E., 1981. The mechanical properties of hydroxypropylmethylcellulose films derived from aqueous systems part 1: the influence of plasticizers. Drug Dev. Ind. Pharm. 7, 649–668. Bajwa, G.S., Hoebler, K., Sammon, C., Timmins, P., Melia, C.D., 2006. Microstructural imaging of early gel layer formation in HPMC matrices. J. Pharm. Sci. 95, 2145–2157. Bhargava, P., Carroll, G.T., Nguyen, T.T., Vaynberg, K.A., 2012. Water Soluble Polymer Powder Formulation Having Improved Dispersing Properties. Hercules Inc.. Bishop, M.D., 1988. Compositions and a Process for Preparing Water Dispersible Polymers. Phillips Petroleum Co.. Bonney, S.R., Ramaile, H.H., 2007. Process of Making Cold-Water Dispersible Cellulose Ethers and Uses Thereof. Hercules Inc.. Bostrom, P., Karlsson, G., 2003. Aqueous Suspension of a Cellulose Ether, Method for the Production Thereof and a Dry Blend. Akzo Nobel N.V.. Bowman, B.J., Ofner, C.M., Schott, H., 2006. Colloidal dispersions. In: Troy, D.B., Beringer, P. (Eds.), Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins, USA, pp. 293–318. Buckton, G., 1988. The assessment, and pharmaceutical importance, of the solid/ liquid and the solid/vapor interface: a review with respect to powders. Int. J. Pharm. 44, 1–8. Callahan, J.C., Cleary, G.W., Elefant, M., Kaplan, G., Kensler, T., Nash, R.A., 1982. Equilibrium moisture content of pharmaceutical excipients. Drug Dev. Ind. Pharm. 8, 355–369. Cook, D.R., Sander, E.H., 1987. Hydroxypropylmethylcellulose. Zumbro Enterprises, Inc.. Doengers, R., Hammes, A., 2004. Method for the Production of Easily Wetted, WaterSoluble, Powdered at Least Alkylated Non-Ionic Cellulose Ethers. Clariant GmbH. Dow, 2002. Methocel Cellulose Ethers, Technical Handbook. Dow, 2012. Cellulose Ethers, Technical Overview and Product Guide. Gupta, P., Nachaegari, S.K., Bansal, A.K., 2006. Improved excipient functionality by co-processing. In: Katdare, A., Chaubal, M.V. (Eds.), Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems. Informa Healthcare, New York, pp. 109–126.

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