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Co-spray drying of metformin hydrochloride with polymers to improvecompaction behavior
Nizar Al-Zoubi a,⁎, Faten Odeh b, Ioannis Nikolakakis c
a Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, Jordanb Department of Pharmaceutical Sciences and Pharmaceutics, Faculty of Pharmacy, Applied Science University, Amman, Jordanc Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Abbreviations: ANOVA, analysis of variance; CSD, co-sdiameter; D90/D10, the ratio of 90th to the 10th percentidesirability; di, individual desirability function; DSC, difER%, elastic recovery; F, breaking force under diametricaemission gun scanning electron microscopy; HPMC, hyIQCS, interquartile coefficient of skewness; m.p., melmoisture content; MF, metformin hydrochloride; MFRMmaterial; Na CMC, sodium carboxymethylcellulosepoyvinylpyrrolidone; PXRD, powder X-ray diffraction; PY(shape index); RTC, ready-to-compress; t, thickness of tTS, tensile strength; TS0.15, tensile strength at porosity ofΔHr, melting enthalpy of metformin hydrochloride raw mofmetforminhydrochloride spray dried powder;ρS, partic⁎ Corresponding author at: Department of Pharm
Technology, Faculty of Pharmaceutical Sciences, HasheJordan.
Article history:Received 30 April 2016Received in revised form 6 September 2016Accepted 23 November 2016Available online 24 November 2016
The ability of different hydrophilic polymers to improve compression behavior of metformin hydrochloride afterco-spray drying from aqueous solutions was investigated. Spray dried products were evaluated by laser diffrac-tion, light microscopy with image analysis, SEM, PXRD, DSC, instrumented press and diametrical loading of com-pacts. The obtained powders consisted of agglomerated spherical particles with median diameters between 6.7and 11.0 μm, and were able to compress after mixing with 7% process aids. Compared with the spray drieddrug alone, co-spray drying with polymers resulted in increase of amorphous content (from 0.5 to between2.0 and 15.6%) associated with increased deformability/interparticle bonding and reduced ejectability. Impor-tance of amorphous content on particle bonding and deformation was confirmed by significant correlation be-tween compaction work and relative crystallinity (p = 0.042). Compactability and tabletability were improvedconsiderably by co-spray drying with the anionic polymers (sodium alginate and sodium carboxymethylcellu-lose), while decreased by co-spray drying with PVP and copovidone compared to spray dried drug alone. Onthe other hand, ejectabilitywas less compromised by co-spray dryingwith copovidone andHPMC. By using over-all desirability scores the polymers were ranked for efficiency in the order: sodium alginate N HPMC N sodiumcarboxymethylcellulose N copovidone N PVP. The plot of tensile strength vs the ratio [work of compaction/(elasticrecovery% × yield pressure)] was a straight line (r = 0.814) allowing prediction of tensile strength from in-diemeasured parameters.
Tableting of high dose active ingredients usually faces problems due totheir poor mechanical properties. In most cases formulators have to usegranulation techniques to obtain drug/excipient agglomerates with suit-able compression properties. However, direct compression is the
le density;Φ, diameter of tablet.aceutics and Pharmaceuticalmite University, Zarqa 13115,
preferredmethodof tableting because it is simple, quick and cost-effective[1]. For this reason, many companies have introduced direct compressiongrades for a number of high dose drugs including paracetamol (e.g.Compap® by Mallinckrodt), ibuprofen (e.g. ibuprofen DC 85® by BASF),ascorbic acid and thiamine HCl. These compressible grades are preparedby various techniques, such as fluid-bed granulation and spray drying,and prior to tableting are usually blendedwith small amounts of other ex-cipients and lubricants to achieve desirable tableting characteristics [2].
Spray drying is a one-step process producing fine or coarse agglom-erated powders, within a narrow particle size range and approximatelyspherical particle shape, with improved compression behavior [3]. Im-proved production efficiency is expected because it is a continuous pro-cess that can be easily automated and suitable for in-line productanalysis [4]. In addition, spray drying reduces time-to-market becauseof scale-upbenefits (manufacturing clinical trial and production batcheson the same equipment) and better quality (minimum batch-to-batchvariations) with obvious economic benefits for the pharmaceutical in-dustry [5].
More importantly, co-processing via spray drying is technologicallyinteresting because the crystalline content may be altered into amor-phous [6]. Therefore, the main application of spray drying is to modify
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the physical form of excipients and drugs for better physico-mechanicalproperties such as flowability, compressibility and compactability [7].However, there are few literature reports addressing the application ofspray drying to improve the mechanical properties of drugs by copro-cessing with different excipients or polymers and the effect of excipientor polymer type [5].
Metformin hydrochloride (MF) is an oral anti-hyperglycaemic agentof the biguanide classmarketed as immediate and sustained release tab-lets with doses ranging from 500 to 1000 mg [8]. Tableting of MF facesproblems of poor compressibility and high tendency for capping, associ-atedwith its high dose, prohibiting direct compression. Therefore, thereis a need in the industry to provide a free-flowingMFpowder capable ofbeing directly compressed into strong tablets to overcome the costlyand time-consuming step of granulation. For this purpose, differenttechniques such as wet granulation [9–11], melt granulation [12], re-crystallization from solution [13–14] have been applied, but to ourknowledge only one attempt by co-spray drying has been reported,using only PVP K30 [15].
Thus, the aim of this study was to prepare co-spray dried (CSD)products of MF with the commercially available polymers sodium algi-nate, sodium carboxymethylcellulose, HPMC, PVP and copovidone,employed at two levels 2.5% and 5%, in order to compare their effecton compression behavior and related physicochemical properties ofobtained powders. The above hydrophilic polymers are known toimprove the compaction of drugs and diluents when coprocessedvia spray drying or granulation [16–18]. Due to their different chem-ical structure, they may interact to different extents with MF mole-cules (through ionic and/or hydrogen bonding), thus inhibitingcrystal growth by inducing lattice defects and amorphicity, that re-sult in improved deformability and compactability. The latter maybe further enhanced by the adhesive effect of the polymer presentin the CSD product.
2. Materials and methods
2.1. Materials
Metformin hydrochloride raw material (MFRM) was purchasedfrom Wanbury LTD (India) and talc from Liaoning Jiayi metals & min-erals (Dalian, China). The following were gifts: sodium alginate(Protanal® LF120M) fromFMCBioPolymer, USA, sodiumcarboxymeth-ylcellulose (Na CMC, Blanose™ 7LF) and hydroxypropyl methylcellu-lose (HPMC, Benecel™ E3 Pharm) from Ashland, USA, PVP (Kollidon®K30), copovidone (Kollidon® VA 64) and crospovidone (Kollidon®CL) from BASF, Ludwigshafen, Germany, and sodium stearyl fumarate(Pruv®) from JRS Pharma, Rosenberg, Germany.
2.2. Preparation of spray dried and co-spray dried batches
Aqueous feed solutions of MFRM with different polymers (Na algi-nate, Na CMC, HPMC, PVP and copovidone) were spray dried using aPulvis mini-spray GA 32 (Yamato Scientific, Japan) equipped with astandard 406 μm two-fluid spray nozzle. First, polymer solutions wereprepared by thoroughly dissolving the polymer in distilled waterunder gentle agitation for 24 h. Then, drugwas added at a drug/polymerratio 97.5/2.5 or 95.0/5.0, mixedwell until completely dissolved and thevolumewas adjusted withwater to a total (drug plus polymer) solidsof 30% w/v. The spray drying conditions were: inlet air tempera-ture130–135 °C, outlet air temperature 95 °C, air pressure 1 kg/cm2
and feed rate 11–14 ml/min. For comparison purposes, aqueousfeed solution of MFRM alone (without polymers) was also spraydried under the same abovementioned conditions. The collectedspray dried products were weighed to calculate the % yield andstored in desiccators over silica gel.
2.3. Characterization of spray dried powders
2.3.1. Powder X-ray diffraction (PXRD)For the characterization of the crystalline state of MFRM and spray
dried powders PXRD patterns were recorded on a Rigaku Ultima IV dif-fractometer (Japan) using a Cu anode operated at 40 kV and 40mA. Thecavity of the sample holder of X-ray diffractometer was filled with sam-ple powder and then smoothed out with a spatula. Samples werescanned at a rate of 4 °C/min from 5 to 80 2θ°.
2.3.2. Differential scanning calorimetry (DSC) and thermogravimetry(TGA)
Thermal analyses andweight loss during heating ofMFRMand spraydried powders were carried out using a DSC-50 differential scanningcalorimeter and a TGA−50 thermogravimetric analyzer, connected toa TA-60-WS controller (Shimadzu Corporation, Kyoto, Japan) for dataacquisition and processing in a computer, using appropriate software(Shimadzu TA60 vs 2.21). For the DSC, 4–6 mg were placed in alumi-num pans, crimped, pierced, and heated under a nitrogen atmosphere(40 ml/min), at a rate of 10 °C/min up to 260 °C. For the TGA, 6–8 mgwere placed in open pans and heated under the same conditions.Weight loss and MC% were estimated from the weight difference at30 °C and at 130 °C after plateau was reached.
From the DSC thermograms the melting peak temperature (m.p.)and the enthalpy of melting, after taking into account sample weight,were obtained. Since DSC has been reported to provide a sensitive andprecise method for quantifying crystalline drug in binary mixtures, itwas used to estimate the relative crystallinity of drug in the spraydried powders. From the melting enthalpy of the spray dried powders,ΔHs, and of the MFRM, ΔHr, the relative crystallinity was calculatedusing the following equation [19–20]:
% relative crystallinity ¼ ΔHs=ΔHrð Þ � 100 ð1Þ
2.3.3. Field emission gun scanning electron microscopy (FEG-SEM)Photomicrographs ofMFRMand spray dried powderswere obtained
using a scanning electron microscope (FEI Company - FEI Quanta 450FEG, Eindhoven, Netherlands). Samples were mounted on aluminumstubs with double-sided sticky discs of conductive carbon and thencoated with approximately 15 nm of platinum in a sputter coater(Emitech K550X, UK).
2.3.4. Particle size, shape and density
2.3.4.1. Particle size. Median particle diameter (D50), width of the distri-bution expressed by D90/D10 and interquartile coefficient of skewness(IQCS) were determined with a laser diffraction particle size analyzerequipped with a dry powder accessory (Mastersizer 2000A, Malvern,UK) using about 1.0 g samples.
2.3.4.2. Particle shape. Roundness (Rn= square of particle perimeter di-vided by 12.56 times the mean projection area) was used as the shapeindex. It represents both geometrical asymmetry and surface irregular-ities and assumes a value of one for a perfect sphere, increasing as theshape deviates. More than 100 particles dispersed in paraffin oil wereexamined at 1000× total magnification using an image processing andanalysis system comprised of: Olympus BX41 opticalmicroscope, Olym-pus U-SPT and Olympus U-PMTVC extensions (Japan); Leica DF295video camera (Germany); computerwith 2009 LeicaMicrosystems soft-ware (Switzerland).
2.3.4.3. Particle density. Particle density (ρS) was determined withhelium pycnometry (Ultrapycnometer 1000, Quantachrome Instru-ments, Boynton, USA) bymeasuring the volume of accurately weighted
Table 1Codes of co-spray dried batches and factors (independent variables) with levels employedin their preparation.
Batch code Polymer type Nominal polymer content (%)
CSD1a Na alginate 2.5CSD1b Na alginate 5.0CSD2a Na CMC 2.5CSD2b Na CMC 5.0CSD3a HPMC 2.5CSD3b HPMC 5.0CSD4a PVP 2.5CSD4b PVP 5.0CSD5a Copovidone 2.5CSD5b Copovidone 5.0
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samples (average of 10 runs) after calibration with a standard7.0699 cm3 steel ball.
2.4. Preparation of ready-to-compress (RTC) mixtures with process aids
RTCmixtures with improved tabletability and ejectability were pre-pared by mixing in 100 ml glass vials for 15 min (Turbula, Bachofen,Switzerland) 25 g of MFRM, MFSD or CSD (93%) with crospovidone(5%, compaction aid), talc (1%, glidant) and sodium stearyl fumarate(1%, lubricant).
2.5. Mechanical properties
2.5.1. Force-displacement profilesFor the evaluation of compaction work required to form a tablet
(WC) an instrumented tablet press (Model GTP-1, Gamlen TabletingLtd., Nottingham, UK) fitted with 6-mm flat-faced punches and operat-ed at 60mm/min and 138.9MPamaximum compressionwas used. RTCpowder mixtures (100 mg) were introduced into the die and force-dis-placement profiles during compression, decompression and ejectionwere recorded. WC was obtained from the area enclosed by the com-pression/decompression curves. The ejection force was also recordedduring tablet ejection and the maximum recorded value (Fej) wasused as an estimate of compact friction and adhesion to the die wall[21].
For the yield pressure (PY) considered as an estimate ofdeformability, and elastic recovery (ER%) as an estimate of elasticity,800mg samples were compressed on a single-punch tabletingmachine(Kilian type KIS, Germany) fitted with 13-mm flat-faced punches, oper-ated at 20 strokes/min and compression pressures up to 160 MPa. Loadcell (LFH-71, RDP Electronics,Wolverhampton, UK) and linear displace-ment transducer (GTX 5000, RDP 1166) were fitted to the upper punch.Electric signals were fed to a polymeter (HS 508, TiePie EngineeringNetherlands) after passing through S-7 DC and E309 signal conditioners(RDP Electronics) and stored in Excel files. Force-displacement profileswere recorded during compression/decompression and PY obtained asthe reciprocal slope of Heckel plots (Eq. (2)) in the range 40–120 MPa:
ln 1= 1−pFð Þ½ � ¼ 1=PYð Þ � Pþ C ð2Þ
where pF is the solids fraction = [compact weight / (volume x particledensity)].
Elastic recovery (ER%) was expressed as the percentage increase intablet thickness after force removal (P=0) comparedwith that atmax-imum punch displacement [22]. Tablet thickness at P = 0 was derivedfrom the corresponding ln[1 / (1 − pF)] by regression analysis, afterfitting a quadratic equation to the points of the decompression phase(in all cases R2 N 0.900).
2.5.2. Tablet tensile strengthRTC powder mixtures (400 mg) were compressed at increasing
pressures into 13-mmdiameter flat-faced tablets on amanually operat-ed hydraulic press (Riken Seiki, Japan). Their breaking force (F) underdiametrical compression was measured with a CT-5 testing machine(Engineering System, Nottingham, UK), at upper platen speed1mm/min. Tensile strength (TS) was calculated from the equation [23]:
TS ¼ 2F=πΦt ð3Þ
where Φ the diameter and t the tablet thickness.Then, compactability plots of TS vs porosity and tabletability plots of
TS vs compression pressurewere constructed. TS values atfixed low po-rosity of 0.15 (TS0.15) was also determined by interpolation as a mid-point in the compactability profile.
2.6. Experimental design and statistical analysis
A mixed-level factorial design (10 runs) with two factors: polymertype at 5 levels and polymer content at two was employed to testtheir effects on the measured properties of the CSD powders. For thestatistical analysis a 2-way ANOVA was applied using the softwareSPSS 20.0 (IBM SPSS Statistics, Inc. Chicago, IL USA). A value ofp ≤ 0.05 was considered as statistically significant. The experimentalbatches are shown in Table 1. For all measurements three samples ofeach batch were tested and the mean value and standard deviation cal-culated. For the goodness of fitting linear correlations, the Pearson coef-ficient (r) was used.
2.7. Classification of polymers performance
The polymers used in the preparation of CSD powders were classi-fied for their ability to improve product quality using desirability func-tion (di) for minimization of shape index (d1) and Fej (d2), andmaximization of tensile strength at low porosity (TS0.15) of tablets(d3). For minimization of di
di ¼ Ymax−Yið Þ= Ymax−Yminð Þ ð4Þ
where Ymin is the lowest, Ymax the highest measured value and Yi an ex-perimental value. For Yi = Ymin, di takes the highest value one, whereasfor Yi = Ymax, becomes zero. Similarly, for maximization of a response.
di ¼ Yi � Yminð Þ= Ymax � Yminð Þ ð5Þ
for Yi = Ymin, di = 0, whereas for Yi = Ymax, di = 1.For the overall performance, the arithmetic average Dav of the indi-
vidual di was used.
Dav ¼Xk
i¼1di
� �=k ð6Þ
where k is the number of the responses (= 3).
3. Results and discussion
Results of production yield, MC%, particle size, shape and density ofdrug spray dried alone (MFSD) and co-spray dried with polymers(CSD1–CSD5) are presented in Table 2, and in Table 3 results of thermalproperties. Results of the mechanical properties of the RTC mixtures ofthe raw drug and all spray dried products are presented in Table 4.
3.1. Production yield and moisture content
Spray dryingwith a lab-scale equipment often results in lowproductrecovery due to sticking of droplets to the walls of the drying chamberand formation of fine particles that are exhausted by the aspirator[24]. From Table 2 it can be seen that for all spray dried products the
Table 2Production yield, moisture content, particle size, shape and density of drug spray driedalone (MFSD) or with different polymers at 2.5 and 5% w/w polymer content (CSD1–CSD5 explained in Table 1).
MCsymbolizesmoisture content, D50median particle diameter; D90/D10 ratio of diameterscorresponding to 90% and 10% of the cumulative undersize particle size distribution; IQCSinter quartile coefficient of skewness; Rnmean particle roundness and ρS particle density.
a SD for ρS b 0.005.
Table 4Mechanical properties of ready-to-compress mixtures of raw drug (MFRM), spray driedalone (MFSD) and co-spray dried with different polymers at 2.5 and 5% polymer content(CSD1–CSD5 explained in Table 1).
WC symbolizes work of compaction; Fej maximum ejection force; PY yield pressure; ERelastic recovery and TS0.15 tablet tensile strength at porosity 0.15.SD for WC 2.0–50.7, Fej 5.5–30.2, PY 0.2–1.4 and for ER% 0.01–0.07.
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yield ranges from 34% (CSD1b and CSD2b) to 84% (CSD3a). The MC% islow from 0.04 (MFSD) to 0.74 (CSD1b), confirming correct choice ofspray drying conditions and drying efficiency. Highest yield (84%) andlowest MC% (0.08), is seen for HPMC at low polymer content (CSD3a),whereas low yield 34% and 54% and large MC% 0.74, 0.40 and 0.73, forNa alginate (CSD1b), Na CMC (CSD2b) and PVP (CSD4b) at high poly-mer content. Therefore, the low yield of the more hydrophilic anionicpolymers and PVP appears to be related to the greater MC% and stickingof the powders to the walls of the drying chamber. However, in addi-tion toMC of final product, nature and properties of polymer have ef-fect on yield. This is supported by ANOVA tests, which revealed thatthe effects of polymer type and content were significant on produc-tion yield (p = 0.010 and 0.020, respectively). The increase in theMC% of the spray dried powders due to higher polymer content issmall, except for Na alginate, and can be attributed to the increasedviscosity of feed solutions (restricted water diffusion from centre ofspray dried droplets) [25] and increased amorphous content as it isshown later (Section 3.3).
3.2. Particle size, shape and density
FromTable 2 it can be seen thatMFSD and CSD powders have similarmedian diameters in the range 6.6–11.0 μm. The ratio D90/D10 (express-ing broadness of size distribution) is between 5.5 and 9.3 and the IQCS(expressing skewness) between 0.16 and 0.27, indicating narrow andpositively skewed distributions (for MFRM: D50 = 158 μm, D90/D10 =
Table 3Thermal properties and relative crystallinity of raw drug (MFRM), spray dried alone(MFSD) or with different polymers at 2.5% and 5% polymer content (CSD1–CSD5 ex-plained in Table 1).
15.9 and IQCS = 0.11). There is no clear or statistically significanttrend of particle size changewith the polymer type or content, implyingthat it is controlled mainly by process parameters, which were all fixedin this study.
In Fig. 1 SEMmicrographs ofMFRM,MFSD and CSDpowders (CSD1–CSD5) are shown. MFRM is composed of large prismatic particles,whereas all spray dried powders are composed of spheroidal particlesexisting as either agglomerates of small particles, or single large parti-cles, with small ones adhered to them. Wrinkles or concavities, are no-ticed on the surface of CSDparticles preparedwithHPMC or copovidone(Fig. 1, CSD3a–b and CSD5a–b).
The values of shape index (Rn) shown in Table 2 are quite large, be-tween 4.67 (CSD1a) and 8.49 (MFSD), because they were derived frommeasurements of the outlines of particle-agglomerates (Fig. 1), ratherthan from individual particles. Therefore, Rn reflects the degree of ag-glomeration. The high Rn of MFSD might be due to the uncontrolledcrystallization and agglomeration. Furthermore, greater Rn is seen atthe high polymer content, which may be attributed to the surface en-richment with polymer and increased agglomeration [26]. An inversesignificant correlation (r = 0.866, p = 0.001) was found between Rnvalues and tap density of spray dried powders (results not shown) indi-cating that smoother particles achieve denser packing. The particle den-sities of all spray dried powders (Table 2) are very close between 1.347and 1.366 g/cm3 (for MFRM, ρs = 1.351 g/cm3).
3.3. Crystallinity and thermal properties
In addition to changes in particle shape, spray drying often leads toformation of amorphous ormetastable crystal forms [27]. TwoMF poly-morphs have been reported, the stable formAwithm.p. near 230 °C anda highly metastable form B [28–29], and PXRD analysis was applied tosee whether spray drying caused any changes in the solid state ofthe drug. In Fig. 2(a–c) representative PXRD patterns of MFRM,MFSD and CSD MF with 5% Na alginate (CSD1b) are shown. Thesharp peaks and absence of halo in the diffraction patterns of MFSD(Fig. 2b) indicate crystalline structure. The positions of the strongdiffraction peaks at x axis are the same for MFRM and MFSD butalso for CSD1b (Fig. 2c) indicating same crystal lattice, which con-forms to form A [29].
However, comparing the PXRDs of MFSD with the CSD1b, differ-ences are seen in the intensity of diffraction peaks in the 2θ region 20tο 40° and some low intensity peaks in the PXRD of the former appearsmaller or disappear in the latter. Different intensities of some peaksof MFRM are also seen in comparison with the MFSD and CSD1b pat-terns, and are partly explained by the preferred orientation of the pris-matic crystals within the sample holder [30]. However, the lower peak
Fig. 1. SEM pictures of metformin HCl raw material (MFRM), spray dried (MFSD) and co-spray dried powders (CSD1–CSD5, explained in Table 1).
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intensities seen for CSD1b than MFSD, with spheroidal particles, shouldbe due to the loss of crystallinity and thermal analysis was performed tofurther elucidate this point [31].
In Fig. 3 representative DSC scans of MFRM, MFSD and CSD with Naalginate at low (2.5%, CSD1a) and high (5%, CSD1b) content are shown.From Table 3, it appears that MFRM and MFSD have m.p. 229.2 and
Fig. 2. PXRD patterns for metformin HCl raw material (a), spray dried (b) and co-spray dried with sodium alginate at 5% polymer percentage (c).
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230.0 °C, corresponding to the stable form [29] indicating that spraydrying does not alter the crystal formwhich is in agreementwith previ-ous reports [6]. Similarly, in Fig. 3 no exothermic peaks appear in the
DSC's of CSD1a and CSD1b but only one melting endotherm, excludingpolymorphic transition. Thus, the decrease of m.p. seen in Table 3 forthe CSD batches is most likely attributed to weakening and disruption
Fig. 3. DSC thermograms of metformin HCl raw material (MFRM), spray dried (MFSD) and co-spray dried with sodium alginate at 2.5% (CSD1a) and 5% (CSD1b) polymer content.
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of crystal lattice and to the presence of amorphous regions formed dur-ing spray drying, which is in agreement with the lower intensity of thepeaks in the PXRD patterns of the CSD products compared to MFSD(Fig. 2).
From Table 3 it appears that the decrease in m.p. of MFRM from230.0 °C is greatest for PVP (CSD4a–b, m.p. 224.0/223.0 °C), lowest forcopovidone (CSD5a–b, m.p. 228.3/228.2 °C) and intermediate for Na al-ginate, Na CMC and HPMC and the effect of polymer type is confirmedby statistical significance (p=0.045). Also (except for Na CMC), the de-crease ofm.p. is higher at high polymer content, implying greater crystaldisruption, confirmed by high statistical significance (p = 0.033).
Fig. 4. Force-displacement profiles obtained for ready-to-compress mixtures of metformin HClcontent (CSD3b).
From Table 3 it is also seen that, on average, the relative crystallinityis lower for the CSD powders with Na alginate (CSD1a–b, 93.8/84.4%),Na CMC (CSD2a–b 93.5/84.8%) and PVP (CSD4a–b, 92.7/90.0%), andgreater for HPMC (CSD3a–b 93.5/93.2%), and copovidone (CSD5a–b,98.0/92.1%). Therefore, from the early melting and the lower relativecrystallinity of the CSD powders compared to MFSD, it can be inferredthat during spray drying the polymers act as crystal growth inhibitorswith Na alginate and Na CMC and the more hydrophilic PVP having agreater impact on drug crystallinity than HPMC and copovidone.
More specifically, the anionic polymers have negatively charged an-ionic carboxyl (−COO−1) groups that can make ionic interactions with
raw material (MFRM), spray dried (MFSD) and co-spray dried with HPMC at 5% polymer
Fig. 5. Heckel plots for ready-to-compress mixtures of metformin HCl raw material (MFRM) and spray dried (MFSD).
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the positively charged ammonium of the drug. Additionally, strong hy-drogen bonds may form between the hydroxyl (−OH) groups of Na al-ginate and Na CMC and the amino (−NH2) or imino (−NH) groups ofthe drug [32]. PVP can associate with the drug via strong hydrogenbonds with carbonyl (NC_O) group and HPMC with weaker hydrogenbonds through the hydroxyl (−OH) groups [33]. The earlier meltingand the greater decrease of crystallinity seen at the higher polymer con-tent (Table 3), can be attributed to increased extent of drug-polymer in-teraction and increased viscosity impairing diffusion of drug moleculesinto the growing crystals [34,35]. The presence of vinyl acetate incopovidone reduces the intensity of hydrogen bonding with drug as in-dicated by highest m.p. of CSD5a, b in Table 3 [36].
3.4. Work of compaction and force of ejection
Work of compaction (WC) relates to the ability of a material to ab-sorb work during compression. In Fig. 4 representative force-
Fig. 6. SEMmicrophotographs for the surface of compressed tablets at highest compression pres(b) at 5% polymer ratio.
displacement profiles for RTC mixtures of MFRM, MFSD or CSD withHPMC 5% (CSD3b) are shown. From these and Table 4 it can be seenthat MFRM shows markedly lower WC than the spray dried powderswhich is in agreement with previous findings and can be explaineddue to the large particle size of MFRM (D50 = 158 μm) compared tofine spray dried powders [37]. This results in lower contact surfacearea and less interparticle friction, and therefore less surface interaction,interparticle bonding and lower WC.
Since all spray dried powders had similar particle size (Table 2), thehigher WC of the CSD powders compared to MFSD (Table 4) should bedue to the presence of polymers on the particle surface. They inhibitcrystal growth promoting creation of amorphous regions, the extentof which depends on the polymer and its content, as indicated by thedifferences in the m.p. and relative crystallinities (Table 3). The pres-ence of amorphous material on the particle surface increases reactivity,contact area, deformability and interparticle bonding, resulting in great-er WC [38–39].
sure (444MPa) formetforminHCl co-spray driedwith sodiumalginate (a) and copovidone
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Considering the data in Tables 3 and 4, it can be seen that batchesCSD1a–b, CSD3b and CSD4a–b with low relative crystallinity (be-tween 84.4 and 93.8%) gave high WC (between 1618.7 and1741.7 mJ) whereas batches CSD5a and MFSD with high relativecrystallinity (98.0 and 99.5%) gave low WC (1557.9 and 1428.3 mJ,respectively). In fact, WC is inversely proportional to both relativecrystallinity (p = 0.042) and m.p. (p = 0.039) emphasizing the im-portance of surface amorphous material on WC [31]. Furthermore,from Table 4 it appears that except for Na CMC, higher polymer con-tent gives higher WC.
Ejection force is important for tableting, related to the difficulty oftablet ejection. High forces caused by friction or adhesion of compactto the die wall impair movement of the lower punch, causing die abra-sion, scratches on the sides of the tablets and chipping at the edges. Thelower Fej seen in Table 4 for MFRM (53 N) should be due to the large
Fig. 7. Tensile strength vs porosity (compactability) and compression pressure (tabletabilitypolymers at 2.5% (a and c) and 5% (b and d) polymer levels.
particle size or small contact area with the die wall and also to the in-ability to form strong, ejection-resistant compact. The lower Fej for theMFSD (87.3 N) seen in Table 4 compared to the CSD batches (114.8–158.2 N) can be attributed to lower adhesion due to the absence ofpolymers.
Considering the CSD batches, it appears fromTable 4 thatNa alginate(CSD1), Na CMC (CSD2) and PVP (CSD4) resulted in higher Fej (146.0 to158.2 N) compared to HPMC (CSD3) and copovidone (CSD5) (114.8 to125.9 N). The effect of polymer type on Fej is significant at p = 0.012and Waller-Duncan post-hoc test defined the above two groups as ho-mogeneous subsets. Since CSD3 and CSD5 batches have similar orhigher Rn values than CSD1, CSD2 and CSD4 (4.67/5.60 and 6.70/6.90compared with 3.67/6.53, 4.81/5.55 and 5.87/6.03, Table 2) theirlower Fej cannot be attributed to particle shape, but to their lowerMC% and reduced stickiness.
) plots for metformin HCl powders prepared by spray drying and co-spray drying with
172 N. Al-Zoubi et al. / Powder Technology 307 (2017) 163–174
3.5. Yield pressure and elastic recovery
In Fig. 5 representative Heckel plots for RTC mixtures of MFRM andMFSD are shown. The curvature of the initial rising phase is due to vol-ume reduction by particle slippage and rearrangement. MFRM withcoarse particles shows higher densification compared to MFSD withfine particles, due to easier packing. The linear rising part that followsis dominated by deformation and is noticed that the graphs of MFRMand MFSD become more distant as compression pressure increases, in-dicating no significant particle breakage but different plastic deforma-tion and yield pressure. The final phase of the graph corresponds todecompression and shows great elastic recovery manifested by a de-crease of 1.5 to 2 densification units which is similar to elastic materialslike starch [40].
The lower PY forMFRMthanMFSD (85.3MPa compared to 65.0MPa,Table 4) is in agreement with many previous findings, reporting de-crease of PY with increasing particle size [41,42]. Although elastic recov-ery may reduce PY, this should not be the main reason for the low PY ofMFRM because MFSD also exhibits high elastic recovery (Fig. 5). There-fore, the low PY of MFRM should be attributed to the reduced density ofdefects and to the lower crack length in the fine MFSD particles,resulting in lower stress concentrations. This means that greater forceswill be needed to initiate crack propagation and fracture [43].
Considering the CSD powders PY is significantly affected by polymertype (p=0.013)with two groups indicated byWaller-Duncan test, oneof low PY: Na alginate (CSD1a–b, 67.6/64.9 MPa), Na CMC (CSD2a–b,55.6/59.9 MPa) and HPMC (CSD3a–b, 62.1/61.0 MPa), and a second ofhigher PY: PVP (CSD4a–b, 80.6/77.5 MPa) and copovidone (CSD5a–b,74.2/83.3MPa). Representative SEMmicrophotographs of tablet surface(Fig. 6) indicate that deformation is greatly involved in the compactionprocess and that Na alginate (CSD1b) is more deformable thancopovidone (CSD5b) which is in agreement with its lower PY (Table 4).
From Table 4 it can be seen that all batches exhibit considerable ER%associatedwith the poor tabletability of the drug. Since ER% is not deter-mined only by rebounding of intraparticle molecular bonds but is alsoaffected by plastic deformation and interparticle bonding, the differ-ences in the ER% cannot be easily explained. However the greater ER%of the MFRM should be associated with its large particle size resultingin smaller number of interparticle contact points per unit area and
Fig. 8. Plots of tensile strength of tablets at 0.15 porosity (TS0.15) against the ratio
therefore less particle bonding and greater rebound after the releaseof applied load [44]. On average, smaller ER% is seen for batches pre-pared with Na alginate (CSD1a–b, 5.3/3.6%) in comparison with NaCMC (CSD2a–b, 5.6/5.3%), HPMC (CSD3a–b, 6.1/5.2%), PVP (CSD4a–b,4.8/6.5%) and copovidone (CSD5a–b, 5.5/5.9%).
3.6. Tensile strength
All spray dried powders gave intact tablets after compressing theirRTC mixtures at pressures between 74 and 444 MPa, whereas MFRMfailed. Compactability plots of tensile strength (TS) vs porosity andtabletability plots of TS vs compression pressure are shown in Fig. 7. Ex-perimental TS values at porosity = 0.15 (TS0.15) are also given inTable 4. Compactability plots are independent of compression rate andcan be used to predict tablet strength,whereas tabletability plots are de-pendent, and useful to assess the effect of tableting speed during formu-lation development [45]. From Fig. 7a–b it is seen that as expected, TSdecreases exponentially with porosity. In comparison with MFSD, co-processing with Na alginate and Na CMC gave stronger tablets, HPMC(at 5% content) tablets of similar strength, while PVP, copovidone andHPMC (at 2.5% content) gave weaker tablets (Fig. 7a–b and Table 4).The polymers' classification is generally in reverse order to that of theyield pressure that has been discussed previously.
From Fig. 7c–d it can be seen that TS increases with compactionpressure up to 444 MPa except for the MFSD and CSD with 5% PVP forwhichmaximum strength is achieved at 369 and 296MPa respectively.The differences in the strength of tablets prepared from different spraydried batches are clearer at high compression pressures (lowporosities)which are usually encountered during the manufacturing of high dosetablets. The differences are more or less the same with those seen inthe compactability plots (Fig. 7a–b).
The effect of polymer on the TS is exerted by altering particledeformability and plasticity due to increased amorphous content butalso through its effect on the strength of interparticle bonds. Differencesin the binding efficiency of polymers incorporated into tablets by fluid-ized-bed or shear granulation have been reported by many workers [9,17]. Addition of binders is expected to enhance compactability and TS.Therefore, since the PY of CSD powders prepared with PVP (CSD4a–b),copovidone (CSD5a–b) and HPMC at low content (CSD5a) are below
of work of compaction to the product of elastic recovery with yield pressure.
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that of MFSD (80.6/77.5, 74.2/83.3 and 62.1 compared with 85.3,Table 4) implying better deformability, the lower TS of their tabletsmay be attributed to reduced strength of the interparticle bonds formedby the polymer. This is in agreement with previous reports of TS de-crease due to addition of binders despite the enhanced plasticity andmay be associated with the greater distribution of polymer on the par-ticle surface migrating during drying [17,38].
Considering the relation between TS and the parameters obtainedfrom in-die measurements during compaction, TS should be propor-tional to the extent of surface bonding and deformation representedby WC, inversely proportional to PY and also to ER%, which representsthe proportion of bonds lost upon removal of the compact from thedie. The proposed relation has been tested in Fig. 8 where it can beseen that the points fall on a straight line (r = 0.814). The equation ofbest fit derived from regression analysis is:
TS0:15 ¼ 0:633 WC= ER%� PYð Þ½ �−0:197 ð7Þ
that can be useful in formulation development for the prediction of tab-let strength from in-diemeasured parameters (TS0.15 and PY inMPa,WC
in mJ).
3.7. Classification of the polymers performance
In Table 5 the individual desirability functions of the spray driedbatches (di) calculated according to Eqs. (4) and (5) for maximizationand minimization, respectively, as well as the overall desirability (Dav,Eq. 6) are presented. Shape indexwas chosen as related to packing abil-ity, maximum ejection force (Fej) as related to ejectability, and tensilestrength at porosity = 0.15 (TS0.15) as a parameter of compactability.
According to the observed response values (Tables 2, 3), the selectedlimits Ymax and Ymin for the calculation of individual desirabilities wererespectively: for d1 (minimization of Rn) 8.49 and 4.67, for d2 (minimi-zation of Fej) 158.2 and 87.3, and for d3 (maximization of TS0.15) 1.62and 5.17. It can be seen that the polymers can be ranked for their abilityto improve product quality in the order: Na alginate NHPMC NNaCMC N
copovidone N PVP, which can be useful during formulationdevelopment.
4. Conclusions
The results of tensile strength demonstrate the possibility toMF tab-lets via spray drying with only 7–12% excipient (0–5% polymer and 7%process aids). Compactability and tabletability can be considerably im-proved by co-spray drying with the anionic polymers (Na alginate andNa CMC), while ejectability was less compromised by co-spray dryingwith copovidone and HPMC.
Table 5Desirability values for the classification of the polymers for their ability to improve theproduct quality.
d symbolizes individual desirability function: for particle roundness (d1); force of ejection(d2); and tensile strength at 0.15 porosity (d3). Dav symbolizes the overall desirability.⁎ MFSD: spray dried alone, CSD1–CSD5 explained in Table 1.
Co-spray drying reduces MF crystallinity to a different extent de-pending on the polymer type. Besides, other factors related to polymerbinding ability and bulk particle mechanical properties are also impor-tant for the strength of tableted composite MF particles.
Based on their overall efficiency to improve product quality(compactability, ejectability and particle shape) the polymers can beranked as: Na alginate N HPMC N Na CMC N copovidone N PVP.
Acknowledgment
The authors would like to thank Dr. Iyad Rashid and Dr. AdnanBadwan (Jordanian Pharmaceutical Manufacturing Company, Amman,Jordan) for the facilitation and help with the use of Gamlen tablet press.This research work received financial support from the Research Coun-cil, Applied Science University, Amman–Jordan.
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