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Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc
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Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc


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Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc - YE SUN,1 JING TAO,1 GEOFF G. Z. …

Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc - YE SUN,1 JING TAO,1 GEOFF G. Z. ZHANG,2 LIAN YU1

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  • 1. Solubilities of Crystalline Drugs in Polymers: An ImprovedAnalytical Method and Comparison of Solubilities ofIndomethacin and Nifedipine in PVP, PVP/VA, and PVAcYE SUN,1 JING TAO,1 GEOFF G. Z. ZHANG,2 LIAN YU11 School of Pharmacy and Department of Chemistry, University of Wisconsin, 777 Highland Avenue, Madison, Wisconsin 537052 Solid State Sciences, Global Pharmaceutical R&D, Abbott Laboratories, North Chicago, Illinois 60064Received 2 February 2010; revised 26 April 2010; accepted 26 April 2010Published online in Wiley InterScience ( DOI 10.1002/jps.22251 ABSTRACT: A previous method for measuring solubilities of crystalline drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug–polymer dispersions, a strategy actively explored for delivering poorly soluble drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of solubility equilibrium. In this method, a drug–polymer mixture prepared by cryo- milling is annealed at different temperatures and analyzed by differential scanning calorimetry to determine whether undissolved crystals remain and thus the upper and lower bounds of the equilibrium solution temperature. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temperatures, but revised slightly the previous results at lower temperatures. It also lowered the temperature of measurement closer to the glass transition temperature. For D-mannitol and IMC dissolving in PVP, the polymer’s molecular weight has little effect on the weight-based solubility. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less soluble than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory–Huggins model, yielding the relevant drug–polymer interaction para- meters. The new annealing method yields more accurate data than the previous scanning method when solubility equilibrium is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate experimental data for developing predictive models. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4023–4031, 2010 Keywords: solubility; amorphous pharmaceuticals; glass transition; polymer dispersion; indomethacin; nifedipine; PVP; PVP/VA; PVAc; DSC; Flory–HugginsINTRODUCTION it is desirable to know the solubilities of drugs in polymers, which define the maximal drug loadingOne approach to delivering drugs that are poorly without the tendency of crystallization.water soluble is to use amorphous drugs in place of At present, there are little data on the solubilities oftheir crystalline counterparts because amorphous drugs in polymers and no standard methods forsolids are generally more soluble and faster dissolving measurement. This situation exists largely because ofthan crystals. A key requirement for any amorphous the high viscosity of polymer solutions, which slowsformulation is that it be stable against crystallization the attainment of solubility equilibrium (equilibriumduring its shelf life. A common strategy for stabilizing between a crystalline solute and its solution). Thean amorphous drug against crystallization is to difficulty is expected to be greater at lower tempera-disperse it in a polymer. To implement this strategy, tures. In the thermodynamic sense, measuring solubility means determining the temperature and the solution Correspondence to: Lian Yu (Telephone: 608-263-2263; E-mail: concentration at which a system achieves Geoff G. Z. Zhang (Telephone: 847-937-4702; E-mail: equilibrium. In reference to the binary phase diagramJournal of Pharmaceutical Sciences, Vol. 99, 4023–4031 (2010) shown in Figure 1, the goal is to determine theß 2010 Wiley-Liss, Inc. and the American Pharmacists Association coordinate (T, w) of a solubility equilibrium e, where T JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 4023
  • 2. 4024 SUN ET AL. T solubility or m.p. the presence of moisture. The moisture presumably depression curve accelerated the establishment of solubility equili- Tm1 brium. A concern with this method is the unknown d effect of moisture on solubilities. It is even possible a b that the absorption of moisture could lower the Tg2 solubility of a hydrophobic solute in a hydrophilic e (T, w) c polymer (anti-solvent effect), causing phase separa- tion of a drug–polymer solution that is otherwise Tg1 thermodynamically stable. Tg There have been attempts to determine the solubilities of crystalline drugs in polymers by 0 w1 (drug) 1 1 w2 (polymer) 0 measuring the dissolution temperatures (depressed melting points) of mixtures of known compositions.4– 6Figure 1. Phase diagram for a drug–polymer system. In these attempts, differential scanning calorime-Point e is a general point on the solubility or melting point try (DSC) is used to detect the equilibrium solutiondepression curve. Lines leading to e show different ways to temperature for a solute–solvent mixture of knownreach solubility equilibrium and measure solubilities. For composition.7,8 To help attain solubility equilibrium,a drug–polymer system, the glass transition temperature Tao et al.6 used cryo-milling to prepare uniformTg can be relatively high so that solubilities need to be drug–polymer mixtures of small particle sizes andmeasured near Tg. performed DSC at slow and various heating rates so that dissolution temperature could be estimated atis temperature and w is concentration. Depending on ‘‘zero’’ heating rate by extrapolation. This methodhow solubility equilibrium is approached, solubility was validated against other solubility-indicatingcan be (and has been) measured in at least four tests and applied to the systems of D-mannitol indifferent ways: (1) follow the increase of solution PVP, nifedipine (NIF) in PVP/VA, and indomethacinconcentration at constant T as the solute dissolves (IMC) in PVP/VA at temperatures approaching theinto an under-saturated solution (path ae); (2) follow glass transition temperatures.the decrease of solution concentration at constant T This study was performed to improve the previousas the solute crystallizes from a super-saturated scanning method6 for measuring drug–polymersolution (path be); (3) measure the dissolution solubilities to increase the likelihood of achievingtemperature or depressed melting point for a solubility equilibrium. Even with the measuressolute–solvent physical mixture of concentration w already implemented, the scanning method could(path ce); and (4) measure the crystallization tem- still have difficulty to achieve solubility equilibriumperature or depressed freezing point for a saturated during the slowest DSC scan practical (approximatelysolution of concentration w (path de). Among these 0.18C/min). In the new method, the sample ismethods, path ae is perhaps the most familiar; it is the annealed near the equilibrium solution temperatureusual procedure for measuring the solubility of a drug and then scanned at a standard heating rate (e.g.,in a low-viscosity solvent. We note, however, that the 108C/min) to determine whether un-dissolved crys-other methods are thermodynamically equivalent. tals still remain. By scanning at a relatively fast rate,Thus, experiments seemingly conducted for other the sensitivity of detecting residual crystalspurposes in fact yield solubilities. For example, the improves. For a drug–polymer mixture annealed atfreezing point of benzene is measured for benzene– different temperatures, the method would yield therubber solutions to study the thermodynamics of upper and lower bounds for its equilibrium solutionpolymer solutions1 and the same data provide the temperature.solubility of benzene crystals in rubber (at T, the The new annealing method yielded results con-solubility of crystalline benzene is its concentration in sistent with those obtained with the previousa solution that ‘‘freezes’’ at T). scanning method at relatively high temperatures, Besides the solubility curve, Figure 1 also shows but revised slightly the previous results at lowerthe glass transition temperature versus concentra- temperatures. It also lowered the temperature oftion curve. This is a reminder that for typical drug– measurement closer to the system’s glass transitionpolymer dispersions, solubilities often need to be temperature. In practice, the two methods can bemeasured near the glass transition temperature, at combined for efficiency. The data collected with thesewhich the approach to solubility equilibrium would be methods show that: (1) for D-mannitol and IMCespecially slow. dissolving in PVP, the polymer’s molecular weight To obtain solubilities of drug crystals in polymers, has relatively little effect on the weight-basedVasanthavada et al.2,3 estimated the solution con- solubility; (2) for IMC and NIF, the dissolving powerscentration after inducing the solute to crystallize in of the polymers tested follow the order PVP > PVP/JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
  • 3. SOLUBILITY OF CRYSTALLINE DRUG IN POLYMER 4025VA > PVAc; (3) in each polymer studied, NIF is actually contained 51.3% w/w NIF in PVP/VA onless soluble than IMC. The activities of IMC and the dry basis. A cryogenic impact mill (SPEXNIF dissolved in various polymers are reasonably CertiPrep model 6750) was used to prepare solute–well fitted to the Flory–Huggins (FH) model, yielding polymer mixtures of different compositions. Liquidthe relevant drug–polymer interaction parameters. nitrogen was the coolant. In a typical procedure, 0.5–The data reported here are not readily anticipated, 1 g of solute–polymer powder was milled at 10 Hz.which underscores the importance of accurate Each cycle of milling was 2 min, followed by a 2 minexperimental data to aid the development of pre- cool down. The cycle was repeated for a total millingdictive models. The method developed here has the time up to 60 min. For D-mannitol–polymer mixtures,potential of providing relevant data for understand- the milling time was 16 min for concentrations aboveing the stability of amorphous drug–polymer disper- 20% w/w; for lower concentrations, the milling timesions. was longer (up to 60 min). For IMC–polymer and NIF–polymer mixtures, the milling time was 12– 16 min.EXPERIMENTAL The milled materials were analyzed by X-ray powder diffraction (Bruker D8 Advance diffract-D-mannitol (99þ%, b-polymorph), IMC (g-poly- ometer with Cu Ka radiation) to assess the potentialmorph), a nonsteroidal anti-inflammatory agent, change of polymorphic form and loss of crystallinity.and NIF (a-polymorph), a calcium channel blocker, For all materials used for solubility measurement,were obtained from Sigma–Aldrich. PVP K15 the crystals that remained after milling were of the(Mw % 8000, 12% w/w moisture) was obtained from original polymorphs (b for D-mannitol, a for NIF,GAF Chemicals. PVP K12 (Mw ¼ 2000–3000, 5% w/w and g for IMC). For this analysis, the sample wasmoisture) and K25 (Mw ¼ 28,000–34,000, 8% w/w ground with mortar and pestle, placed on a zero-moisture) were obtained from BASF. The ‘‘VP dimer’’ background Si(510) sample holder, and scanned[1,3-bis(2-pyrrolidone-1-yl) butane, Mw ¼ 222.3] was from 2 to 508 (2u) at a speed of 18/min and a step sizeobtained from ISP (Wayne, New Jersey). PVP/VA of 0.028.(Kollidone VA64, Mw ¼ 45,000–70,000, 5% w/w moist- Differential scanning calorimetry was conductedure) was obtained from BASF. It was a 60:40 vinyl in hermetic aluminum pans using a TA Instrumentspyrrolidone-vinyl acetate copolymer (Tg ¼ 1018C). DSC Q2000. Three pin holes were made in the lid toPVAc (Mw % 83,000, 2% w/w moisture) was obtained allow the escape of moisture. For annealing, 5–15 mgfrom Sigma–Aldrich in the form of beads (Scheme 1). of sample was packed into a pan and annealed at a Solute–polymer mixtures of desired concentrations desired temperature from 4 to 10 h. The sample waswere prepared by weighing the components. Each then cooled and scanned at 108C/min to determineconcentration was corrected for the amount of water whether residual crystals remained after annealing.present in the polymer; as a result, what is referred to Unless otherwise noted, the reported Tg is the onsetlater as 50% w/w NIF in PVP/VA, for example, temperature of the glass transition. CH2OH H O OH CH3 N CH3 HO CH O H3CO OCH3 HO CH N O O HC OH NO2 O HC OH CH2OH Cl D-mannitol Indomethacin (IMC) Nifedipine (NIF) CH3 CH3 C C O O N O N O O O H H H H C C C C co C C C C H H n H H H H n H H n PVP PVP/VA PVAc Scheme 1. Structures of chemical substances used in this study.DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
  • 4. 4026 SUN ET AL.RESULTS AND DISCUSSION well the drug and polymer components have been mixed and the viscosity of the solution in whichNew Annealing Method Versus Previous Scanning solubility equilibrium is to be established. BetterMethod mixing of components can shorten the time required to reach solubility equilibrium.6 For the mixturesIn the previous scanning method, we start with a studied here, we used the longest cryo-milling timecrystalline drug dispersed in a polymer and heat the possible; for NIF and IMC, this means stopping justmixture to measure the drug’s solution temperature before all solute crystals were rendered amorphous.Tend. This process corresponds to the path cd in As to the viscosity effect, the required annealing timeFigure 1. To improve the ease of achieving solubility is expected to increase as the solution viscosityequilibrium, cryo-milling is used to prepare uniform increases. For a particular drug–polymer combina-drug–polymer mixtures of small particle sizes, tion, this occurs as the equilibrium solution tempera-thereby minimizing the diffusive mixing necessary ture approaches the glass transition temperature offor dissolution. We also use slow and various scan the saturated solution (Fig. 1).rates so that Tend can be estimated at ‘‘zero’’ scan rate The annealing time used in this work was up toby extrapolation. 10 h. This choice was made in part because we decided If solubility equilibrium can be achieved at point e to perform the entire analysis (both annealing andduring the DSC scan, the measured Tend is the scanning) in the same DSC instrument. Although aequilibrium solution temperature T. If not, Tend is separate oven could be used for annealing, the DSChigher than T, which leads to underestimation of chamber has the advantage of precise and stablesolubility. In the new method, isothermal annealing temperature control and constant N2 purge tois used to increase the time for equilibration. If the minimize chemical decomposition. With this choice,annealing temperature is below T (e.g., point c in Fig. it was impractical to anneal for much longer times. As1), crystals will remain even after long annealing and we show below, our annealing time proved sufficientthe subsequent scan of the sample will show a for many drug–polymer mixtures, for the resultsdissolution endotherm. If the annealing temperature obtained in this work agree with those obtained withis above T (e.g., point d), no crystals will remain after the previous scanning method, indicating the longersufficiently long annealing and the subsequent scan equilibration time provided by the annealing methodwill show no dissolution endotherm. By varying the was unnecessary. For limited systems tested, equili-annealing temperature, one can use this method to brium appeared to be attained during our annealingestablish the lower and upper bounds of the time. We do not claim, however, that our annealingequilibrium solution temperature (in the case time is suitable for all systems under all conditions,described, Tc < T < Td). especially as Tend further approaches Tg. In this method, the presence or absence of residual Figure 2 shows typical data collected to implementcrystals after annealing is determined by DSC at a the constant–concentration–variable–temperaturestandard heating rate (e.g., 108C/min). The use of a annealing scheme. A 40% w/w IMC in PVP/VArelatively high heating rate improves the sensitivity mixture was annealed at 102 or 1058C for 4 h andof detecting residual crystals. then scanned at 108C/min. The first thermal event is Besides the annealing protocol just described,another scheme can be envisioned: rather thanannealing the same mixture at different tempera- -0.15 After 4 hrs at 102 ºCtures, mixtures of different compositions can be Tg Heat flow, w/gannealed at the same temperature T. If the mixture -0.2composition is below the solubility at T (e.g., point a in After 4 hrs at 105 ºC ∆H = 0.9 J/gFig. 1), no crystals will remain after sufficiently long -0.25annealing and the subsequent scan will show nodissolution endotherm. If the mixture composition is -0.3above the solubility at T (e.g., point b), crystals willremain even after long annealing and the subsequent 20 40 60 80 100 120 140 160scan will show a dissolution endotherm. By varying T, ºCthe mixture composition, one can obtain the lower and Figure 2. DSC traces of 40% w/w IMC/PVP/VA mixtureupper bounds for the solubility at T (in the case annealed for 4 h at 102 and 1058C. Tg is the glass transitiondescribed, wa < w < wb). temperature. No significant amount of crystals were The time to anneal a drug–polymer mixture must detected after annealing at 1058C, but crystals remainedbe long enough for the system to reach solubility after annealing at 1028C. Increasing the annealing time atequilibrium. Assuming no chemical degradation (see 1028C to 10 h did not change the amount of residual crystalsbelow), the required annealing time depends on how within the error of DSC.JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
  • 5. SOLUBILITY OF CRYSTALLINE DRUG IN POLYMER 4027the glass transition. The sample annealed at 1058C 180showed no other thermal event, whereas the sample 160 Tendannealed at 1028C showed an additional endotherm. 140This difference is interpreted as resulting from the 120complete dissolution of crystals at 1058C and incom- T, °C 100 (a) D-mannitolplete dissolution at 1028C. Increasing the annealing 80 in PVPtime at 1028C to 10 h did not eliminate the residual 60crystals; the change of the dissolution endotherm 40appeared to be within the error of DSC (estimated to Tgbe Æ0.3 J/g for a 1 J/g thermal event). In this work, we 20treated 105 and 1028C as the upper and lower bounds 0 10 20 30 40 50 60 70 80 90 100for the equilibrium solution temperature Tend for the % w/w D-mannitolmixture studied. It is relevant to note that this 180particular mixture (40% w/w IMC in PVP/VA) is one (b) NIF in PVP/VA 160 Tendof the most difficult to equilibrate in this study 140because of the small difference between Tend and Tg. Figure 3 compares the results of the scanning and T, °C 120annealing methods for the three systems studied. For 100D-mannitol dissolving in PVP K15, the annealingmethod yielded consistent results as the scanning 80 Tgmethod6 (Fig. 3a). This consistency suggests that for 60this system, the scanning method is sufficiently 40accurate, for the longer equilibration provided by the 0 10 20 30 40 50 60 70 80 90 100annealing method did not alter the results signifi- % w/w NIFcantly. It also follows that the annealing time chosen 160was adequate for the system to reach equilibrium. (c) IMC in PVP/VA For the systems NIF in PVP/VA and IMC in PVP/ 140 TendVA, the annealing method yielded results consistent 120with those obtained with the scanning method at T, °Chigher temperatures, but revised slightly the results 100at lower temperatures (Fig. 3b and c). The agreement 80between the two methods at higher temperaturessuggests that the longer annealing of the new method 60 Tgwas unnecessary and that the annealing time used 40was sufficient for the system to reach equilibrium. For 0 10 20 30 40 50 60 70 80 90 10030% and 40% w/w NIF in PVP/VA, the solution % w/w IMCtemperatures obtained with the annealing method Figure 3. Comparison of Tend obtained with the scanningare ca. 78C below those obtained with the scanning (circles, Ref. 6) and annealing (crosses, this work) methodsmethod. The same observation was made for 40% and for three systems. The two crosses at each concentration are50% w/w IMC in PVP/VA. the upper and lower bounds of Tend. The lower curves are The greater difference between the results of the glass transition temperatures. For the D-mannitol–PVPscanning and annealing methods at lower drug mixtures, Tg is the inflection point because the onset tem-concentrations (Fig. 3b and c) is probably due to perature is difficult to define at high polymer concentra-the closeness of the equilibrium solution temperature tions; for the other mixtures, Tg is the onset temperature.and the glass transition temperature of the saturatedsolution. If dissolution takes place in a highly viscoussystem, solubility equilibrium may be too slow to of D-mannitol, on the other hand, are present afterestablish during the time scale of DSC scans. Because longer milling (up to 60 min), which could lead to morethe new annealing method allows longer equilibra- intimate mixing of components and easier attainmenttion times, its results should be more accurate. of solubility equilibrium. The better agreement between the annealing and In an alternative annealing scheme, mixtures ofscanning methods in the case of D-mannitol dissolving different concentrations were held at the samein PVP (Fig. 3a) than NIF and IMC dissolving in PVP/ temperature to determine the lower and upperVA (Fig. 3b and c) may have to do with the limited bounds for the solubility at the annealing tempera-milling times (12–16 min) that could be used for the ture. The lower- and upper-concentration mixturesIMC and NIF systems, because longer milling were chosen to bracket a guessed solubility value.rendered these solutes fully amorphous. The crystals In this way, we determined that the solubility ofDOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
  • 6. 4028 SUN ET AL.D-mannitol in PVP K15 is between 20% and 30% w/wat 1308C, the solubility of NIF in PVP/VA is between 15030% and 40% w/w at 1238C, and the solubility of IMC Tendin PVP/VA is between 50% and 60% w/w at 1108C. PVP K15These results are consistent with those of the 100 PVP K12constant–concentration–variable–temperature PVP K15 VP dimermethod (Fig. 3b and c). T , °C 50 Between the two versions of the annealing method, PVP K12 Tgthe constant-concentration-variable-temperaturescheme seems the preferred. It is more convenient 0to vary temperature precisely in small increments VP dimerthan to vary the composition of drug–polymer -50mixtures precisely in small increments. In practice,a small number of mixtures at different compositions 0 20 40 60 80 100can be prepared and each mixture tested at precisely % w/w D-mannitoland finely controlled temperatures. This seemspreferred over making many mixtures at small and Figure 4. Tend and Tg versus D-mannitol concentration inprecise composition increments and testing them at a PVP K15 and PVP K12, and the VP dimer. Tg is the inflection point because the onset temperature is difficultfew fixed temperatures. to define at high polymer concentrations. The annealing method is expected to be moreaccurate than the scanning method for measuring results from the scanning method and be the moredrug–polymer solubilities at low temperatures. In definitive method at lower temperatures. For thepractice, the two can be combined for efficiency: the solution temperature from the scanning method, thescanning method is used for a quick assessment of the average value of at least two measurements issolubility–temperature curve and the annealing 170method is used for more accurate measurements at IMClow temperatures. 150 TendPossibility of Chemical Degradation During Annealing 130 PVAcThe new annealing method involves longer heating of 110 T, °C PVP/VA ◄ ◄drug–polymer mixtures at various temperatures PVP K25 PVP K12below the drug’s melting point. A relevant question 90is whether chemical degradation occurs during this + PVP K25treatment. Forster et al.9 reported that IMC does not 70 ◊ PVP K12decompose significantly upon melt–extrusion with x PVP/VA Tg 50 ♦ PVAcPVP or PVP/VA at zone temperatures up to 1708C.Zhu et al.10 reported that IMC does not decompose 30significantly upon melt–extrusion with Eudragit at 0 20 40 60 80 100zone temperatures up to 1408C. Aso et al.11 reported % w/w IMC 180that NIF–PVP mixtures are chemically stable uponheating to 1908C. For the polymers used in this study, NIFour annealing temperatures do not seem excessive.12 160 TendWe have also observed that even after the longest 140 PVAcannealing, there was no significant change of the PVP/VA 120 ◄sample’s glass transition temperature, which is PVP K12 T, °Cconsistent with the lack of significant decomposition. 100These observations provide some assurance of che-mical stability of our materials against heating; 80 ◊ PVP K12however, they are not direct proof of chemical x PVP/VA 60stability under the conditions of this study. ♦ PVAc Tg 40Comparison of Solubilities 0 20 40 60 80 100Figures 4 and 5 summarize the solubility data % w/w NIFmeasured in this study and from Ref. 6. Both thescanning and the annealing methods have been used; Figure 5. Tend and Tg versus concentration for mixturesthe annealing method was applied to check the of IMC or NIF with various polymers.JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
  • 7. SOLUBILITY OF CRYSTALLINE DRUG IN POLYMER 4029reported; for the solution temperature from the importance of accurate experimental data forannealing method, the lower bound value from at developing predictive models.least two measurements is reported; the differencebetween replicate measurements is less than 28C. The Solute Activity and Flory–Huggins Interactionnew data include the solubilities of D-mannitol in PVP Parameter xK12 and the VP dimer and of IMC and NIF in PVPand PVAc. With these data, two comparisons are The solubility of a crystalline drug in a polymer allowsmade below. the calculation of the drug’s activity a1 in the saturated solution: (1) Solubilities of D-mannitol in PVP of different ln a1 ¼ ðDHm =RÞ ð1=Tm À 1=TÞ (1) molecular weights: It is of interest to learn how the solubility of the same solute varies in poly- where Tm is the melting point of the pure drug, DHm is mers of different molecular weights. Figure 4 its molar heat of melting, and T is the temperature at compares the solubilities of crystalline D-man- which the drug’s solubility is measured (or its nitol in PVP K15 (Mw % 8000), PVP K12 depressed melting point). Figure 6 shows the result (Mw % 2500), and the VP dimer (Mw ¼ 222.3). of this calculation for IMC and NIF dissolving in The VP dimer was included here because it has different polymers. In each case, the solute activity been used as a small-molecule solvent for esti- decreases with the increase of polymer weight mating drug solubilities in PVP. The low visc- fraction w2. The rate of this decrease, however, osity of the VP dimer (it is a viscous liquid at depends strongly on the polymer used. For the room temperature) allowed its solubility to be polymers studied, PVP reduces the activity of the measured down to 5% w/w with our method. solute the most, in keeping with its highest dissolving Figure 4 shows that if expressed in % w/w, power, followed by PVP/VA and then by PVAc. We the solubilities of crystalline D-mannitol are note that this comparison is not made across polymers comparable in PVP of various molecular of the same molecular weight, although the change of weights. The more limited data for IMC (see the PVP molecular weight by ca. 10-fold (from K12 to later) are consistent with this conclusion. These K25) has little effect on the solubility of IMC. results suggest a possibility of using a small- molecule solvent to estimate the solubilities in 1 polymers. Given the difficulty of measuring the IMC solubility of crystalline solutes in polymers, 0.8 especially at low temperatures, the use of small-molecule solvents for estimating solubi- 0.6 lities in polymers is of considerable interest. (2) Solubilities of IMC and NIF in different poly- a1 mers: We next compare the solubilities of IMC 0.4 and NIF in two homo-polymers (PVP and PVAc PVAc) and their co-polymer (PVP/VA). For both 0.2 PVP/VA solutes, the solubilities follow the order PVP PVP K25 PVP K12 (most soluble) > PVP/VA > PVAc (least solu- 0 0 20 40 60 80 100 ble). The solubilities of IMC in PVP K12 and w2 PVP K25 (expressed in % w/w) are comparable, 1 which is consistent with a similar observation made for the D-mannitol/PVP system (Fig. 4). NIF 0.8 The different dissolving powers of PVP (high- est), PVP/VA, and PVAc (lowest) for IMC and NIF apparently contradict the notion ‘‘like dis- 0.6 solves like.’’ If IMC and NIF are considered a1 hydrophobic substances, they should be less 0.4 soluble in more hydrophilic solvents. Mean- while, PVP is considered more hydrophilic than 0.2 PVAc PVP/VA PVP/VA and PVP/VA is considered more hydro- PVP K12 philic than PVAc. (PVP is more hygroscopic 0 than PVP/VA.) Thus, one would expect the 0 20 40 60 80 100 w2 solubility trend to be PVP (lowest) < PVP/ VA < PVAc (highest), precisely the opposite of Figure 6. Activity of IMC or NIF a1 versus polymer our observation. This inconsistency shows the weight fraction w2. The solid curves are FH fits.DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
  • 8. 4030 SUN ET AL. If the Flory-Huggins (FH) model1 is applied to the version of our method provides even longer equilibra-drug–polymer solutions studied here, the activity of tion time to improve the likelihood of achievingIMC or NIF in the solution is given by solubility equilibrium. Together, these measures   likely have provided more accurate results, especially 1 at low temperatures. ln a1 ¼ ln v1 þ 1 À v2 þ xv2 2 (2) x Concerning the stronger interaction between IMC and PVP, PVP/VA, or PVAc than between NIF andwhere v1 is the volume fraction of IMC or NIF, v2 is the same polymers, one possible explanation is thatthe volume fraction of the polymer, x is the molar IMC can form hydrogen bonds with the polymers.volume ratio of the polymer and the drug, and x is the IMC has a good hydrogen bond donor, whereas NIFdrug–polymer interaction parameter. The solid has none. PVP, PVP/VA, and PVAc have no goodcurves in Figure 6 are the results of fitting the hydrogen bond donors, but have hydrogen bondactivities to the FH model. In this analysis, we have acceptors. Taylor and Zografi13 found using infraredassumed that the volume fraction is the same as the spectroscopy that IMC and PVP can hydrogen bond. Itweight fraction and the parameter x is the ratio of the would be of interest to establish how useful thismolecular weights of the polymer and the drug. hydrogen-bonding analysis is for understanding The FH model fits the data in Figure 6 reasonably drug–polymer solubilities.well. In contrast, the model does not give a good fit of One utility of the FH analysis is that if the model isthe activity of D-mannitol in PVP (result not shown). applicable, it could be used to predict4,5 the drug–To the extent the reasonable fitting in Figure 6 polymer solubility at lower temperatures, at whichjustifies the use of the FH model, the interaction direct measurements would be more difficult. It isparameters x could be obtained for various drug– important, however, to first verify the validity of thispolymer pairs and compared. The x values thus model and ensure the accuracy of the drug–polymerobtained (Table 1) suggest that for each solute (IMC interaction parameters. This study found that the FHor NIF), the interaction with PVP is the strongest, model can fit reasonably well the activities of IMC andfollowed by PVP/VA, and then by PVAc, and that for NIF dissolved in PVP, PVP/VA, and PVAc, whereas iteach polymer studied, the interaction with IMC is fits poorly the activity of D-mannitol dissolved in PVP.stronger than that with NIF. Where comparable, our x values are substantiallymore negative (indicating stronger attractive inter- Future Studiesactions) from those of Marsac et al.5 (Table 1, last Given the difficulty to achieve solubility equilibriumcolumn). This difference probably results from the in polymer matrices, it is worthwhile to considerdifferent experimental conditions of the two studies. additional ways to improve the technique of measure-Marsac et al. used a scanning method to measure ment. Larger DSC pans could be used to increase thepolymer-depressed melting points of crystalline amount of sample and the sensitivity of detecting thedrugs; their sample was a physical mixture of a drug crystals that remain after annealing. Annealingand a polymer (or a drug and a drug–polymer times could be systematically varied to define optimaldispersion); their DSC scan rate was 18C/min. In values for different annealing temperatures. Chemi-our method, cryo-milling is used to improve the cal analysis could be performed to determine whetheruniformity and reduce the particle size of drug– chemical degradation occurs during long annealing.polymer mixtures so that solubility equilibrium is More systems could be tested and compared tomore easily achieved. In the scanning version of our develop models for prediction.method, slow and various heating rates are used sothat melting point depression can be estimated at‘‘zero’’ heating rate by extrapolation. The annealing CONCLUSIONS We have developed a new annealing method toTable 1. Drug–Polymer Interaction Parameters x complement the scanning method previouslyDrug Polymer x (This Work)a x (Ref. 5) reported for measuring the solubility of crystalline drugs in polymers. In this method, cryo-milling is usedNIF (a form) Tm ¼ 1728C, PVPK12 À2.5 Æ 0.2 0.0 to prepare uniform drug–polymer mixtures of small DHm ¼ 39.9 kJ/mol5 PVPVA64 À1.8 Æ 0.2 — PVAc À0.02 Æ 0.03 — particle sizes to facilitate the attainment of solubilityIMC (g form) Tm ¼ 1608C, PVPK12 À8.2 Æ 0.6 À0.82 equilibrium. Samples are annealed at various tem- DHm ¼ 39.7 kJ/mol5 PVPK25 À8.0 Æ 0.7 — perature to achieve phase equilibrium and then PVPVA64 À4.5 Æ 0.3 — scanned at a standard heating rate (108C/min) to PVAc À0.41 Æ 0.02 — determine whether un-dissolved crystals remain. a Values after the Æ sign are standard deviations of fitting. For a drug–polymer mixture annealed at differentJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
  • 9. SOLUBILITY OF CRYSTALLINE DRUG IN POLYMER 4031temperatures, the method yields the upper and lower 2. Vasanthavada M, Tong W, Joshi Y, Kislalioglu MS. 2004. Phasebounds for its equilibrium solution temperature. behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility. Pharm Res 21: The new annealing method yielded results consis- 1598–1606.tent with those obtained with the previous scanning 3. Vasanthavada M, Tong W, Joshi Y, Kislalioglu MS. 2004. Phasemethod at relatively high temperatures, but revised behavior of amorphous molecular dispersions II: Role of hydro-slightly the previous results at lower temperatures. It gen bonding in solid solubility and phase separation kinetics.also lowered the temperature of measurement closer Pharm Res 22:440– the glass transition temperatures. In practice, the 4. Marsac PJ, Shamblin SL, Taylor LS. 2006. Theoretical and practical approaches for prediction of drug–polymer miscibilitytwo methods can be combined for efficiency. The data and solubility. Pharm Res 23:2417–2426.collected with these methods show that (1) for D- 5. Marsac PJ, Li T, Taylor LS. 2008. Estimation of drug–polymermannitol and IMC dissolving in PVP, the molecular miscibility and solubility in amorphous solid dispersions usingweight of the polymer has relatively little effect on the experimentally determined interaction parameters. Pharm Respercent-by-weight solubility; (2) for IMC and NIF, the 26:139–151. 6. Tao J, Sun Y, Zhang GGZ, Yu L. 2009. Solubility of small-dissolving powers of the polymers tested follow the molecule crystals in polymers near the glass transition tem-order PVP > PVP/VA > PVAc; and (3) in each polymer perature: D-mannitol in PVP, indomethacin in PVP/VA, andstudied, NIF is less soluble than IMC. The activities of nifedipine in PVP/VA. Pharm Res 26:855–864.IMC and NIF dissolved in various polymers are 7. Park K, Evans JMB, Myerson AS. 2003. Determination of solubility of polymorphs using differential scanning calorime-reasonably well fitted to the Flory-Huggins model, try. Cryst Growth Des 3:991–995.yielding the relevant drug–polymer interaction para- 8. Tamagawa R, Martins W, Derenzo S, Bernardo A, Rolembergmeters. The data reported here are not readily M, Carvan P, Giulietti M. 2006. Short-cut method to predict theanticipated, which underscores the importance of solubility of organic molecules in aqueous and nonaqueousaccurate experimental measurements to aid the solutions by differential scanning calorimetry. Cryst Growthdevelopment of predictive models. The method Des 6:313–320. 9. Forster A, Hempenstall J, Rades T. 2001. Characterization ofdeveloped here has the potential of providing relevant glass solutions of poorly water-soluble drugs produced by meltdata for understanding the stability of amorphous extrusion with hydrophilic amorphous polymers. J Pharmdrug–polymer dispersions. Pharmacol 53:303–315. 10. Zhu Y, Shah NH, Malick AW, Infeld MH, McGinity JW. 2006. Controlled release of a poorly water-soluble drug from hot-melt extrudates containing acrylic polymers. Drug Dev Ind PharmACKNOWLEDGMENTS 32:569–583. 11. Aso Y, Yoshioka S, Kojima S. 2004. Molecular mobility-basedWe thank Abbott Laboratories and NSF (DMR- estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions. J0907031) for supporting this work. Pharm Sci 93:384–391. 12. Rowe RC, Sheskey PJ, Quinn ME. 2009. Handbook of pharma- ceutical excipients. 6th edition. American PharmaceuticalREFERENCES Association. Washington: Pharmaceutical Press, London. 13. Taylor LS, Zografi G. 1997. Spectroscopic characterization of 1. Flory PJ. 1953. Principles of polymer chemistry. Ithaca, NY: interaction between PVP and indomethacin in amorphous Cornell University Press. molecular dispersions. Pharm Res 14:1691–1698.DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010