Construction of Drug–Polymer Thermodynamic Phase Diagrams

Oct 30, 2012 - Pharmaceutical Development, AstraZeneca, Silk Rd Business Park, Macclesfield, SK10 2NA ..... Giovanna C.R.M. Schver , Dajun D. Sun , Sa...
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Construction of Drug−Polymer Thermodynamic Phase Diagrams Using Flory−Huggins Interaction Theory: Identifying the Relevance of Temperature and Drug Weight Fraction to Phase Separation within Solid Dispersions Yiwei Tian,† Jonathan Booth,‡ Elizabeth Meehan,‡ David S. Jones,† Shu Li,† and Gavin P. Andrews*,† †

The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre, Queen's University, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, United Kingdom ‡ Pharmaceutical Development, AstraZeneca, Silk Rd Business Park, Macclesfield, SK10 2NA ABSTRACT: Amorphous drug−polymer solid dispersions have the potential to enhance the dissolution performance and thus bioavailability of BCS class II drug compounds. The principle drawback of this approach is the limited physical stability of amorphous drug within the dispersion. Accurate determination of the solubility and miscibility of drug in the polymer matrix is the key to the successful design and development of such systems. In this paper, we propose a novel method, based on Flory−Huggins theory, to predict and compare the solubility and miscibility of drug in polymeric systems. The systems chosen for this study are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCASHF)−felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl caprolactam−polyvinyl acetate−polyethylene glycol)−FD. Samples containing different drug compositions were mixed, ball milled, and then analyzed by differential scanning calorimetry (DSC). The value of the drug−polymer interaction parameter χ was calculated from the crystalline drug melting depression data and extrapolated to lower temperatures. The interaction parameter χ was also calculated at 25 °C for both systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems obtained at this temperature was comparable. Diagrams of drug−polymer temperature−composition and free energy of mixing (ΔGmix) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing solid dispersions at specific drug loadings. Three different samples for each polymer were selected to represent different regions within the phase diagram. KEYWORDS: drug−polymer thermodynamic phase diagrams, Flory−Huggins interaction theory, HPMCAS-HF−felodipine, Soluplus−felodipine, high-speed differential scanning calorimetry

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INTRODUCTION Over the past decade, formulations containing amorphous drugs have become extremely attractive due to the significant enhancement in solubility and dissolution rate that may be achieved.1−3 The apparent aqueous solubility of the drug once incorporated into a dispersed system can be significantly higher than its crystalline counterpart.4−6 However, drugs in an amorphous state are inherently unstable and tend to crystallize during storage and/or dissolution.7 A common strategy for increasing the solubility and stability of an amorphous drug is to disperse it in a polymeric matrix, thus forming an amorphous solid dispersion. Melt extrusion, spray drying, and other relevant techniques may be used to obtain an intricate blend of drug and polymer. To make full use of a solid dispersion strategy, knowledge of the drug solubility and drug−polymer miscibility in the matrix of choice is necessary. The conventional approach to selecting a suitable polymeric carrier to form an amorphous drug solid dispersion may involve several steps, © 2012 American Chemical Society

including investigation of a range of drug loadings for each polymer candidate, identification of the most suitable preparation method, and selection of appropriate processing conditions.8,9 In doing so, one aims to achieve the most suitable processing conditions and drug/polymer ratio to promote mixing between drug and polymer and thus improve stability. One important point to consider is that attainment of a onephase system requires the two components to be thermodynamically miscible during processing. Furthermore, because solid dispersion preparation may take place at nonambient temperatures and/or in the presence of solvent (e.g., melt extrusion and spray drying), perturbation of the system during processing can lead to dynamic system that re-equilibrates Received: Revised: Accepted: Published: 236

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postprocessing.10 Consequently, a more logical and rationale approach would be to better understand the degree of drug over/undersaturation in the polymeric matrix as a function of temperature and how this can be linked to the molecular structure and physical properties of both components. In particular, it would be useful to identify drug−polymer combinations that form strong adhesive interactions using simple experimental methods and to use this information to guide the selection of appropriate drug loadings and processing conditions, to maximize stability of the amorphous solid dispersion. Previously, we reported a method based upon small-scale differential scanning calorimetry (DSC) measurements wherein the Flory−Huggins (F−H) interaction parameter could be determined from physically mixed drug/polymer mixtures.11 The Gibb's free energy of mixing (ΔGmix) was not favorable when χ was positive, indicating immiscibility. Conversely, when χ took a negative value, the ΔGmix was negative, suggesting miscibility between drug and polymer. In this current article, we wanted to extend our understanding of F−H interaction theory relative to drug−polymer miscibility and to determine whether this approach could be used in a more overarching manner to understand the thermodynamics of drug−polymer mixing during processing and better inform our choice of polymeric carrier in future melt extrusion studies. More specifically, we wanted to build upon our previous work and construct phase diagrams that provide information through which we can understand the relationship between drug composition, temperature, and phase separation. We aimed to offer information on the solubility and miscibility of the drug within the polymeric matrix. Development of appropriate phase diagrams that offer significant correlation between experimental measurements and end product performance (physical stability) would undoubtedly expedite early stage formulation development. To date, there have been limited articles describing the use of theoretical calculations to determine the solubility/miscibility of the drug within polymer matrices and hence define phase stability.12 Equally, there is a clear deficit of articles describing the use of experimental methods to predict the drug−polymer phase boundaries. What has been published is largely restricted to solubility determination in low molecular weight liquid monomers and/or oligomers.10,13,14 In so doing, the apparent solubility of the drug in the short chain system (monomer/ oligomer) may be predicted by using the drug activity coefficient γ, which acts as a bridge connecting the interaction parameter χ and drug solubility. One significant drawback of this approach is the assumption that the molecular environment of the drug within the short chain system adequately represents that in the solid polymeric matrix. Furthermore, aside from polyvinypyrrolidone and related polymers (vinyl acetate copolymers), obtaining small chain oligomeric equivalents for pharmaceutical polymers is difficult without custom synthesis. There are a number of interesting articles that have reported using the endset melting point depression to obtain a constant drug−polymer interaction parameter χ that may be used to construct the binary phase diagrams.15−17 Interestingly, the interaction parameter, χ, is considered temperature independent. More recently, χ has been shown to be not only concentration dependent but also temperature dependent.18,19 In light of this information, within this article, we have developed this theory to construct phase diagrams that are relevant to both temperature and drug composition and thus

provide information relevant to practical manufacture of solid amorphous drug dispersions. In this study, we provide a practical approach that is based upon melting point depression data and F−H theory to construct drug−polymer binary phase diagrams. Using melting point depression data, the temperature dependence of interaction parameter may be calculated for drug and amorphous polymer mixtures.20,21 These parameters may be used to establish miscibility between drug and polymer as a function of temperature and composition. Given the increasing importance being attached to drug−polymer miscibility within the pharmaceutical arena and the potential correlation to physical stability, it is imperative that such phase diagrams are better understood. Moreover, the increasing trend to manufacture solid dispersions using nonambient technologies such as melt extrusion make it even more important to define a drug−polymer−temperature framework in which miscibility and solubility of drug within the respective polymer be defined. In this paper, we present, for the first time, a constructive and critical evaluation of an experimental method that may be used for the construction of drug−polymer phase diagrams and provide a relevant discussion on how these phase boundaries can be used to evaluate polymeric materials during the preparation of solid dispersions. The model drug selected in this study was felodipine (FD). Two polymeric carriers commonly used in the production of melt extrudates were selected, namely, hydroxypropyl methylcellulose acetate succinate HF grade (HPMCAS-HF) and a graft copolymer of polyvinyl caprolactam−polyvinyl acetate−polyethylene glycol (Soluplus). Theoretical Considerations. According to F−H theory, the Gibb's free energy change that accompanies mixing of a drug−polymer binary system may be expressed as: ΔGmix = ΔHmix − T ΔSmix

(1)

Subsequently, the Gibb's free energy may be expressed as a function of the F−H interaction parameter, χ: ⎛ ϕdrug ⎞ ϕpoly ΔGmix = RT ⎜⎜ ln ϕdrug + ln ϕpoly + χdrug − poly ϕdrug ϕpoly ⎟⎟ N N ⎝ A ⎠ B

(2)

where ϕ is the volume fraction, N is the molecular volume of the drug or polymer, χ is the F−H interaction parameter, R is the molar gas constant, and T is the temperature. In a drug− polymer mixture, we may define NA as the molecular size of the drug, in which case NB = mNA, where m is the ratio of the volume of a polymer chain to drug molecular volume (eq 3): M w(poly)

m=

ρpoly M w(drug) ρdrug

(3)

where the Mw(poly) and Mw(drug) are the molecular weight of polymer and drug, respectively, and the ρpoly and ρdrug are the density of polymer and drug, respectively. The free energy of mixing for a drug−polymer binary system may therefore be written alternatively as: ⎛ ⎞ ϕpoly ΔGmix = RT ⎜⎜ϕdrug ln ϕdrug + ln ϕpoly + χdrug − poly ϕdrug ϕpoly ⎟⎟ m ⎝ ⎠

(4)

The free energy of mixing (ΔGmix) may therefore be calculated at a specified temperature with respect to the corresponding interaction parameter. Furthermore, melting 237

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Figure 1. Chemical structure of (a) FD, (b) Soluplus, and (c) HPMCAS. “m”, “n”, and “I” represent the number of repeat units within each respective polymer. In HPMCAS, n = 75; in Soluplus, n = 13, m = 30, and I = 57.

binary systems, then ΔGmix versus composition and temperature may be constructed simply by combining eqs 4 and 5 with eq 7. Furthermore, the maximum drug−polymer miscibility boundary (spinodal curve) may be calculated by determining the second derivative of the free energy (eq 4) and setting equal to zero as shown in eq 8:

point depression data collected from DSC may be used to predict the drug−polymer interaction parameter using the following equation:14,17 ⎛ 1 1 R ⎡ 1⎞ − =− ⎢ln ϕdrug + ⎝⎜1 − ⎠⎟ϕpoly ⎣ ΔH Tm Tm0 m ⎤ + χdrug − poly ϕpoly 2 ⎥ ⎦

1 1 + − 2χdrug − poly = 0 ϕdrug mpoly ϕpoly

(5)

where ϕ is the volume fraction of the drug, Tm and Tm0 are the melting points of the drug crystal in the drug/polymer mixture and the pure drug, respectively, R is the gas constant, and ΔH is the heat of fusion of the drug. It should be noted that the interaction parameter is not constant but temperature and composition dependent.22−25 To develop a phase diagram to accommodate variation in temperature, we define the temperature dependence of the drug−polymer interaction parameter χ as shown in eq 6: χdrug − poly = A +

B + C1ϕ + C2ϕ2 T

where the interaction parameter χ can be substituted from eq 7. Thereby, the maximum drug−polymer miscibility curve may be obtained.18

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MATERIALS AND METHODS Materials. FD with a purity of 99.9% was a gift from AstraZeneca (Macclesfield, United Kingdom). HPMCAS-HF was supplied by Shin-Etsu Chemical Co. (brand name AQOAT). Polyvinyl caprolactam−polyvinyl acetate−polyethylene glycol graft copolymer (brand name Soluplus) was a generous gift from BASF Chemical Co. (Ludwigshafen, Germany). The chemical structures of these ingredients are shown in Figure 1. Methods. Sample Preparation. Drug and polymer mixtures with different compositions were first mixed using a mortar and pestle followed by a ball mill mixer (Retsch, model MM200, Germany). In a typical procedure, drug and polymer powder sample totaling 1 g was milled inside the container with one stainless steel ball at 20 Hz. A predefined milling time of 2 min was chosen, which was subsequently followed by a 2 min interval. This procedure was repeated to a maximum of up to 10 mill-stop cycles (max 20 min mill time) to determine optimum milling conditions. Thermal Analysis. Power compensation DSC (DSC8000, Perkin-Elmer, United Kingdom) was used throughout this study. Nitrogen was used as the purge gas for low speed scanning; helium gas was used for high speed scanning. A 5−10 mg powder sample was packed into an aluminum pan with a lid. A pinhole was made in the lid to allow the moisture to escape. Before conducting the experiments, all ball-milled samples were dried in a vacuum oven for at least 24 h. Melting depression experiments were conducted at heating rate of 1 °C/min from 20 to 200 °C. The end point of the melting endothermic peak was calculated from the intercept point of the endothermic trace and the postmelting baseline. Given that

(6)

where A is the value of the temperature-independent term (entropic contribution), B is the value of the temperaturedependent term (enthalpic contribution), and C1 and C2 are fitting constants of χ with respect to volume fraction. This relationship subsequently has been simplified (eq 7) and has proven to be sufficient in many polymer−polymer systems exhibiting an upper critical solution temperature (UCST): χdrug − poly = A +

B T

(8)

(7)

wherein the dependence of χ on volume fraction (composition) is negligible relative to temperature.18 This first order relationship between χ and temperature is an additional assumption of F−H polymer solution theory, which summarizes the nontrivial dependencies of χ on polymer composition, chain length, and temperature. More recently, the variation of the relationship between χ and temperature has been previously reported,26,27 and the first order relationship between χ and 1/ T has been used to extrapolate the value of χ for drug−polymer binary systems outside experimental temperatures.19,28 In this study, we have employed eq 7 that relates χ to temperature and used this to identify F−H constants A and B. If the relationship between χ and T within a given temperature range can be determined for certain drug−polymer 238

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Table 1. Physical Properties of FD, HPMCAS, and Soluplus molecular volume (cm3/mol) FD HPMCAS Soluplus

a

300.19 14007.78b 116161.62b

MW (g/mol)

density (g/cm3)

384.25 18000 115000

1.28 1.28 0.99

solubility parameterc (MPa)1/2

ΔHfusion (kJ/mol)

24.39 32.10 31.22

26.03

a

a

Data reported in the literature.10 bValues calculated by dividing molecular weight by true density. cSolubility parameters were calculated using the group contribution method.

parameters is provided by Barton.29 In this study, the van Krevelen group contribution method has been used to calculate the solubility parameter, which may be expressed as:

the drug−polymer particle surface interaction is a critical requirement for melting point depression experiments, different milling cycles were tested to achieve the optimal depression results. From initial experiments, it was shown that increasing the milling time up to four cycles (8 min of milling time) resulted in an increased melting depression. Thereafter, no further melting depression was observed during increased cycle load (data not shown). Therefore, 8 min of milling time was selected for all samples. Annealing experiments were used to corroborate drug− polymer phase diagrams. Drug−polymer solid dispersions were first prepared via a solvent evaporation method. Clear drug− polymer solutions at specified compositions were prepared, and the solvent was removed using a rotary evaporator (Büchi, Germany). Following rotary evaporation, the resulting amorphous solid dispersion samples were then left in a vacuum oven at room temperature to allow any residual solvent to escape. The prepared solid dispersion was then annealed for 24 h in the DSC at predefined temperatures (guided by drug− polymer phase diagrams). Once annealed, the sample was fast cooled at a rate of 200 °C/min to −60 °C and then heated at 200 °C/min to 200 °C to determine the phase composition of the system. The thermal stability of drug−polymer mixtures during annealing was determined using thermogravimetric analysis (TGA) (TA Instruments, United Kingdom). Approximately 10 mg of sample was weighed and heated at 20 °C/min to a temperature 5 °C higher than the highest annealing temperature and held at this temperature for 24 h. Weight losses of only 0.2 wt % (approximate) were recorded after annealing. To characterize the Tg of a freshly prepared drug−polymer solid dispersion, ball-milled drug−polymer mixtures of varying composition were held for 5 min in the DSC furnace at a temperature above that of the melting temperature of pure drug. Subsequently, samples were fast cooled to −60 °C to form an amorphous solid dispersion and immediately heated, at a rate of 200 °C/min, up to 200 °C. This cool−heat cycle was performed at least twice until a constant Tg value was obtained; this value was used to represent the Tg of freshly prepared amorphous solid dispersions. Powder X-ray Diffraction. The solid-state properties of ballmilled samples were determined using a MiniFlex II powder Xray diffractometer (Rigaku, United States). Radiation was generated from a copper source operating at a voltage of 40 kV and a current of 40 mA. The test samples were packed into a glass sample holder and scanned from 0° to 40° 2θ, using a step width of 0.01° 2θ and a scan rate of 1° 2θ per minute; continuous mode was used. Prediction of Solubility/Miscibility Using Drug and Polymer Solubility Parameters. Solubility parameters are often used when predicting the miscibility or compatibility of a mixture, and this technique is well established in polymer− solvent/polymer−polymer solution studies. A comprehensive discussion of solubility parameters and other cohesion

δtotal =

δd 2 + δp2 + δ h 2

(9)

where and δd, δp, and δh are the components of disperse forces, polar group forces, and hydrogen bond energy, respectively. These may be calculated as follows: δd =

∑ Fdi ; V

δp = a

∑ Fp2 V

;

δh =

∑ E hi V

(10)

Fdi is the group contribution to the disperse forces, Ehi is the group contribution to hydrogen bonding energy and Fpi is the plane symmetry factor of polar groups.29 V is the group contributions to molar volume. The drug−polymer interaction parameter χ therefore may be calculated as follows:18 χ=

V0 (δdrug − δpoly )2 RT

(11)

where V0 is the volume of the lattice site. The molar volumes of a single polymer unit calculated from the group contributions were used for the HPMCAS−FD and Soluplus−FD systems, respectively. As shown in eq 11, χ refers to the square of the difference in solubility parameters that were calculated from the values of group contributions at 25 °C. The drug−polymer interaction parameters for these two systems as calculated from solubility parameters were used for comparison with results obtained from melting point depression experiments. The solubility parameters of Soluplus, HPMCAS-HF, and FD have been calculated using a group contribution method. The values of Fdi, Fpi, and Ehi of each group at 25 °C used in this work were chosen from van Krevelen's solubility parameters.30 The hygroscopicity of the components were ranked as Soluplus > HPMCAS > FD. Therefore, the plane symmetry factors of polar group contributions in Soluplus, HPMCAS-HF, and FD were selected at 0.5x, 0.25x, and 0x, respectively. The physical properties and solubility parameters of the materials used in this study are summarized in Table 1.

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RESULTS AND DISCUSSION Drug−Polymer Miscibility Using Solubility Parameters. Solubility parameters were estimated using the Hoftyzer and Van Krevelen method and are provided in Table 1. The values obtained for Soluplus and HPMCAS were very similar, 31.22 and 32.10 MPa1/2, respectively, whereas FD had a solubility parameter that was significantly lower (24.39 MPa1/2). The use of solubility parameters to guide drug− polymer miscibility, in the context of hot melt extrusion, has been previously reported.31 It is well-known that compounds with similar solubility parameters (∼7 MPa1/2) are more likely to be miscible, whereas compounds with solubility parameters differing by more than 10 MPa1/2 are most probably immiscible. In our case, the difference between the solubility 239

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Figure 2. DSC thermograms of ball-milled mixtures measured at a heating rate of 1 °C/min containing (a) HPMC-AS and FD from top to bottom: 100, 95, 90, 85, 80, 75, 70, 60, and 55% w/w FD, respectively. (b) Soluplus and FD from top to bottom: 100, 95, 90, 85, 80, and 75% w/w FD, respectively.

melting.28 In a similar fashion, should polymer and drug interact during processing, the chemical potential and thus the melting point of the drug would be reduced. Consequently, DSC may be employed to investigate the miscibility between drug and polymer to better understand and predict the performance of amorphous solid dispersions. Previously, it has been reported that the solubility of a drug within a polymeric matrix can be determined by measuring dissolution temperatures (endset points) of known drug−polymer compositions.15,16 It is extremely important to recognize that two processes are occurring simultaneously, amorphous drug induction and drug−polymer interaction. In this study, we have used the melting endset point to measure the temperature of the dissolution end point of the drug in each respective polymer.17 At this point, the depression in melting endset as a

parameter of FD and both polymers was small (∼7 MPa1/2). For FD and HPMCAS, the difference was 7.71 MPa1/2, and for FD and Soluplus, the difference was 6.83 MPa1/2. This would suggest that FD and Soluplus have a higher miscibility than the FD and HPMCAS, and further thermal analysis should be conducted to examine the possibility of forming a glass solution.31 In this study, thermal analysis was used to construct a drug composition versus temperature diagram that would be beneficial in offering further understanding of drug−polymer miscibility and physical stability. F−H Interaction Parameter and Gibb's Free Energy of Mixing. During solid state processing, for example, ball milling, the amorphous-to-crystalline drug ratio may be altered. In this case, milling may increase the amorphous content of the drug, lower its chemical potential, and hence depress the drug 240

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result of adding polymer, relative to milled FD (1/Tm − 1/ Tmo), may be used along with eq 5 to calculate χ.19 Because the endset point of melting may be depressed at increased milling frequency and duration, it is necessary to determine the optimum milling conditions to maximize the potential interaction between two components. The correct use of ball milling within a suitable time scale will potentially increase the particle surface interaction and deliver more accurate melting point depression data. The optimum milling time was determined to be 16 min, comprising four cycles of 2 min of milling and 2 min interval. At processing times exceeding 16 min, no further melting point depression was observed. Figure 2 shows the DSC thermograms obtained for the ballmilled samples containing different weight fractions of drug. Clearly, there is significant evidence of melting point depression, suggesting a substantial degree of mixing at the melting temperature. The endset of melting for FD decreased with an increasing fraction of HPMCAS or Soluplus. The effects were greater for Soluplus than HPMCAS. To further understand drug−polymer miscibility, we estimated the F−H interaction parameter by rearranging eq 5. A plot of (1/Tmmix − 1/Tmpure) × (ΔHfus/−R) − ln(φdrug) − (1−1/m)φpolymer versus φpolymer2, as shown in Figure 3a, yielded a linear relationship. For HPMCAS−FD, an interaction parameter with a value of

+0.37 (r2 = 0.99) was obtained, whereas for the Soluplus−FD system, an interaction parameter with a value of −0.37 (r2 = 0.99) was obtained. In the case of HPMCAS, the positive value of χ is indicative of the weak interactions between drug and polymer. This is characterized by the limited melting point depression data observed and athermal mixing (Figure 3a). For Soluplus−FD, the negative χ value is representative of a miscible system and an exothermic heat of mixing. Conversely, large positive interaction values are typically observed for immiscible systems.13 It should be noted that the values obtained for the interaction parameter are both very close to zero. Soluplus is slightly negative and suggests that this polymer may exhibit more favorable mixing than HPMCAS at temperatures close to the melting point of FD. The values of the interaction parameter (χ) for these systems are less informative with respect to phase separation of drug from the polymer as a function of temperature and drug composition. To extend this discussion, we used eq 4 and the values of the F−H interaction parameter to examine the change in Gibb's free energy as a function of drug fraction (Figure 3b). The Gibb's free energy for both systems was negative and was dependent upon drug volume fraction. Interestingly, the Gibb's free energy plots suggest that both polymers would be miscible with FD, with Soluplus, as expected, displaying a lower Gibb's free energy value. The negative Gibb's free energy is not entirely surprising given that this plot provides an overall indication of mixing between the drug and the polymer at temperatures close to the melting point of the drug. Consequently, we can infer that during a nonambient processing method such as melt extrusion, we would be likely to produce a miscible drug and polymer system. However, from this information, we have no indication of the likelihood of mixing at temperatures lower than the drug melting point. For example, using the above information, it would be hard to determine the level of drug−polymer miscibility to be expected at room temperature and hence whether phase separation is likely. One should note that at room temperature, the system would most likely be below the Tg of the system and may be kinetically hindered from recrystallization. However, with the appropriate phase diagram, we should, at least from a thermodynamic standpoint, be able to determine if recrystallization would be favorable. Moreover, given that the difference in solubility parameters of FD and both polymers was close to 7 MPa1/2, we would argue that both systems are miscible but expect concentration- and temperature-dependent miscibility.31 In this case, within the following sections, we provide a useful extension of this theory to provide a temperature/composition phase diagram. Construction of Temperature−Composition Phase Diagrams. Melting depression data collected from DSC experiments was fitted to eq 5 to determine the interaction parameter as a function of temperature. At drug compositions less than, 0.70 for Soluplus−FD, and 0.55 for HPMCAS−FD, no melting event was observed. Assuming drug−polymer binary systems exhibit an UCST, the temperature dependence of the interaction parameter may be described as first order as shown by eq 7. A plot of interaction parameter versus 1/T is shown in Figure 4. For the Soluplus−FD system, a linear relationship between 1/T and χ was observed across the experimental composition range from 0.85 to 0.70. In this case, the correlation coefficient, r2, was determined to be 0.99. The HPMCAS−FD system displayed a linear relationship at drug compositions from 0.70 to 0.55. The r2 value was determined to

Figure 3. (a) F−H interaction plot used to determine the FH interaction parameter close to the melting point of the drug. (b) A plot of ΔGmix/RT as a function of drug volume fraction. The filled symbols represent data calculated using the interaction parameter derived from panel a, whereas the open symbols represent data using the interaction parameter derived from eq 7 at a temperature close to the melting point of pure drug (140 °C). 241

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polymer miscibility predicted by the solubility parameter method and melt point depression method resulted with χ for Soluplus−FD being less than HPMCAS−FD (Table 2). The values obtained for F−H interaction parameter constants “A” and “B” were subsequently used in eq 7, so that we could obtain values of χ at different temperatures. As previously reported by our group, the value of the interaction parameter significantly affects the Gibb's free energy of mixing.11 In this article, we have clearly shown that at 25 °C the interaction parameter for these drug polymer systems is positive (immiscible), whereas at higher temperature, miscibility is promoted. Substituting the interaction values calculated at different temperatures into eq 4, we can begin to understand the variation in Gibb's free energy of mixing (ΔGmix) as a function of drug composition and temperature. This information is useful in understanding whether specific drug−polymer compositions will spontaneously phase separate. Plotting the free energy of mixing for the HPMCAS−FD and Soluplus−FD binary systems (Figure 5a,b), it is apparent that

Figure 4. Variation of the interaction parameter X as a function of temperature. The solid line represents the line of best fit of eq 7 to experimental data.

be 0.88. At drug concentrations higher than 0.7 for HPMCAS and 0.85 for Soluplus, a nonlinear relationship was observed. Nonlinearity between 1/T and χ has been previously reported at high drug loadings in the indomethacin/PVP-VA system.28 This suggests that within specific polymer−drug blends, the interaction parameter may be dependent upon higher order concentration terms (e.g., shown in eq 6).18,19 One important point to consider is that nonlinearity occurs at high drug loadings, at small values of 1/T, and hence high temperature. Consequently, at temperatures of interest with respect to pharmaceutical stability (20−60 °C), the relationship between temperature and χ may be assumed to follow a first order relationship. Moreover, at high temperature because the χ value obtained by experiments is lower than that used from F−H theory, we know that the phase boundaries (drug solubility and drug miscibility) determined from this relationship would be underestimations with respect to drug concentration. Given this assumption, we were able to obtain values for F−H constants A and B, as described within eq 7 (Table 2). Using this method, Table 2. F−H Interaction Constants A and B Determined Using Linear Regression Analysis of Experimental DSC Data and Interaction Parameter, χ, Calculated at 25°C Using Melting Depression and Solubility Parameter Methods A B χa χb

FD + HF system

FD + Soluplus system

−18.767 7830.4 7.509 4.122

−14.419 5744.7 4.856 2.725

a

Determined through extrapolation of melting point depression data to 25 °C. bCalculated using van Krevelen solubility parameter method at 25 °C.

Figure 5. (a) Plot of ΔGmix/RT as a function of drug volume fraction for FD and HPMCAS at temperatures of 25, 50, 80, 100, 120, and 140 °C. (b) Plot of ΔGmix/RT as a function of drug volume fraction for FD and Soluplus at temperatures of 25, 50, 80, 100, 120, and 140 °C.

we have calculated the interaction parameter, χ, at 25 °C for both the Soluplus and the HPMCAS system. The interaction parameters for the two systems at 25 °C were also calculated using solubility parameter method (eq 11, χb in Table 2). The drug−polymer interaction parameter χ, for each system, irrespective of the calculation method, was positive. This suggests limited miscibility existed between FD and HPMCAS or Soluplus and FD at a temperature of 25 °C. As expected, the value of the interaction parameter decreased at elevated temperature. Most importantly, a similar rank order of drug−

at a temperature of 140 °C, the ΔGmix of both systems is negative and convex. At this elevated temperature, homogeneous mixtures are generated that are thermodynamically stable at all drug−polymer compositions. As shown in Figure 5a,b, the temperature at which the Gibb's free energy became positive was dependent upon the polymer used and the volume fraction of the drug. 242

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For the HPMCAS−FD system temperatures ≤120 °C resulted in a ΔGmix/RT that became positive at high drug loadings. The drug composition at which the Gibb's free energy became positive decreased as temperature decreased. For Soluplus−FD, temperatures of ≥100 °C resulted in a negative ΔGmix/RT at all drug−polymer ratios. As the temperature decreased (≤80 °C), the Gibb's free energy of mixing became positive at drug volume fractions >0.3. The calculated solubility and amorphous−amorphous miscibility results for FD in HPMCAS and Soluplus are summarized, together with the predictions from the solubility parameter method, in Table 3. Table 3. Prediction of the Solubility and Miscibility of FD in HPMCAS and Soluplus Polymeric Systems at a Temperature of 25 °C maximum values solubility of FD (%wt) 25 °C solubility of FD (%wt)b 25 °C miscibility of FD (wt%) 25 °C 50 °C 80 °C 100 °C a

HF system

Soluplus system

0.001 0.60

0.02 3.69

7 10 14 22

12 18 31 58

a

Determined through calculation of melting point depression data to 25 °C. bCalculated using van Krevelen solubility parameter method at 25 °C. Figure 6. (a) Binary phase diagram for FD and HPMCAS, annealed at 113 °C, with three different drug loadings (wt %): 25, 44, and 64%. (b) Binary phase diagram for FD and Soluplus, annealed at 103 °C, with three different drug loadings (wt %): 36, 55, and 72%.

At positive values of ΔGmix, the system may spontaneously phase separate to lower its energy level. As the temperature increases, the enthalpic contribution term (χdrug−polyφdrugφpoly) in eq 4 decreases due to a reducing positive value of χ for the HPMCAS and Soluplus systems investigated in this study. Additionally, at 25 °C, the drug composition at which ΔGmix = 0 defines the miscibility limit between drug and polymer under specified conditions. Understanding how ΔGmix varies as a function of T for each system allows drug solubility and miscibility to be plotted as a function of drug weight fraction and temperature. This information may be further combined with the glass transition temperature to obtain phase diagrams as shown in Figure 6a,b for the HPMCAS−FD and Soluplus−FD systems, respectively. The temperature−composition phase diagram based on F−H theory offers a framework from which we can better understand the performance of the FD within the respective polymeric matrices. In essence, the phase diagram allows one to predict the maximum solubility of the drug and, the miscibility of amorphous drug, in the specified amorphous polymer carrier as a function of temperature. The glass transition curve used in Figure 6 has been constructed from data derived from freshly prepared amorphous solid dispersion samples, below which the molecular mobility will decrease dramatically. The correlation between the molecular mobility and the crystallization diffusion coefficient of an amorphous solid has been discussed elsewhere.32 Interestingly, below the Tg, should phase separation be thermodynamically favored, the characteristics of the polymeric platform (Tg, G’, G”, Ea to pass Tg) may offer significant kinetic barriers to recrystallization, thus stabilizing the system over pharmaceutical relevant time scales. The drug solid−liquid phase boundary indicates the fraction of crystalline FD dissolving into the respective polymeric carrier as a function of both temperature and composition, while the dashed line, refers to the spinodal curve. To the right-hand-side of the

spinodal curve the drug is present within the polymer in an unstable state whereas to the left-hand-side of the spinodal curve the drug is present in a metastable state. In the metastable zone, the system will be stable to small fluctuations however large fluctuation in drug density will result in drug recrystallization via a nucleation and growth mechanism. Within this region, nucleation will be prevented until a significant energy barrier is overcome. This is especially true when the temperature is below the glass transition of the system. To the right-hand side (higher drug concentration) of the spinodal curve, from a thermodynamic perspective, phase separation would be favored. Relative to HPMCAS−FD systems, the temperature− composition curves of Soluplus−FD shifted toward the high composition range, indicating the higher solubility and miscibility of FD in the Soluplus system. Using this method to predict phase boundaries provides detailed information on potential processing windows, indicating a maximum metastable region in which to formulate an amorphous solid dispersion system. Additionally, the phase diagrams also identify regions in which large energetic barriers (kinetic hindrance) to recrystallization are apparent, that is, thermodynamically favored and kinetically hindered systems. Given the increasing interest in nonambient processing (melt extrusion or spray drying) of solid dispersions, the phase diagrams generated for both polymers would be of high relevance in defining the temperature and drug composition at which the mixture is locally stable and/or phase separates. In being able to define such, we can use phase diagrams to provide conditions for maximum interaction between the two components. Additionally, once the system returns to room temperature, we can 243

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The first validation point involved the selection of two systems within the metastable zone; that is, it was below the solid−liquid curve. In this case, we manufactured a 25% FD/ HPMCAS dispersion and a 36% FD/Soluplus dispersion and annealed for 24 h at temperature 113 and 103 °C for HPMCAS and Soluplus, respectively. At these conditions, both systems exist at drug concentrations exceeding thermodynamically favorable molecular mixing but within a miscibility limit. As shown in Figure 8, both systems exhibited two glass transitions. For the Soluplus−FD system, glass transitions were observed at approximately 56 and 88 °C. The lower Tg value is very close to that of amorphous drug, implying a drug-rich phase, whereas the higher temperature transition could be perceived to contain a higher proportion of polymer, thus elevating the Tg to 88 °C. Within the HPMCAS−FD system, two glass transition events were also observed, at approximately 71 and 88 °C. Again, we expect the lower transition event to represent a phase containing a greater drug proportion. The identification of two glass transitions for both HPMCAS and Soluplus systems in this region suggests that the free energy landscape permits decomposition of the mixture into two liquid phases rather than direct transformation to amorphous polymer and crystalline drug. To further understand the phase boundaries, a Soluplus dispersion containing 55% FD and a HPMC-AS dispersion containing 44% FD were manufactured and annealed under previously described conditions. These drug loadings were selected as they represented drug volume fractions slightly beyond the spinodal curve, that is, within the unstable region for both systems. A glass transition was observed for both polymeric systems and a small endothermic transition indicative of low levels of crystalline drug within the matrix (ΔH = 0.31 J/g for 55% FD−Soluplus and ΔH = 0.69 J/ g for 44% FD−HPMCAS; the expansion of melting endotherms is shown within Figure 7). At the highest drug weight fractions (64% for HPMCAS and 72% for Soluplus), a glass transition was observed in both cases. This transition was lower than the Tg of the polymer, suggesting that amorphous drug was still present, while large endothermic peaks were observed in addition to the glass transitions (ΔH = 27.1 J/g for 72% FD−Soluplus and ΔH = 40.1 J/g for 64% FD− HPMCAS). These results confirm the existence of increased crystalline drug within the polymeric dispersions in which drug exists in a supersaturated state that has a high thermodynamic driving force toward recrystallization. In this high drug-loaded region, since we are beyond the spinodal decomposition curve, spontaneous crystallization occurs in the absence of any significant energy barrier.

assess whether this brings the system to a state of thermodynamic instability wherein the drug is oversaturated within the polymer. In such cases, the development of formulations possessing high kinetic barriers to recrystallization could be used as a method of stabilization over pharmaceutical relevant time scales. Validation of Temperature−Composition Phase Diagram. Crystallization from the amorphous state is an extremely complex process and dependent upon thermodynamic factors, storage conditions (humidity, temperature), and other kinetic factors.33 In this study, we wanted to evaluate constructed phase diagrams by examining the thermal stability of selected drug−polymer ratios at predefined temperatures. In all validation work, HyperDSC was used. Given that molecular mobility of a drug below the Tg is limited and even further restricted following dispersion within a high viscosity polymer, evaluation of constructed phase diagrams was conducted by annealing samples in the DSC at temperatures exceeding the Tg for a 24 h period. While we recognize that above the Tg, drugs are kinetically hindered by other factors such as viscosity and drug−polymer interactions, the propensity for recrystallization at T > Tg, where there is global mobility within the platform, is undoubtedly greater. Three drug−polymer compositions were chosen for each polymer system, based on the temperature− composition diagrams shown in Figure 6a,b (see Table 4). The Table 4. Drug−Polymer Dispersions Used for Validation of Phase Diagrams

FDHPMCASa FDSoluplusb comments

metastable zone

unstable supersaturated zone ϕdrug = x

unstable supersaturated zone ϕdrug = y, y > x

25 wt %

44 wt %

64 wt %

36 wt %

55 wt %

72 wt %

Recrystallization expected within the metastable and unstable zone but less likely in metastable region.

Drug percentage validated at 113 °C. bDrug percentage validated at data at 103 °C. a

phase diagrams that we have constructed exhibit two critical curves, a solid−liquid phase curve and a maximum drug− polymer miscibility curve (δ2ΔG/δϕ2 = 0), often referred to as the spinodal decomposition curve. The solid−liquid phase curve has been determined from melting point depression data. Above this curve, the system is one phase; hence, this represents the maximum solubility of the drug within the polymer. Theoretically, the metastable zone, which may be defined as the region above the drug−polymer miscibility curve and below the solid−liquid curve,27 is likely to produce a drug polymer system that is metastable and stable to small fluctuations in drug concentration. Clearly, kinetic effects are greater at temperature < Tg. The DSC was carefully calibrated at a scanning speed (200 °C/min) using the melting temperatures of indium and zinc as reference standards. Helium was used as the purge gas to enhance the thermal conductivity of the sample and DSC cell environment during heating. The high scanning speed power compensation DSC provided more accurate data in sample scanning, especially in identifying the existence of the amorphous−amorphous metastability.34,35 Typical HyperDSC results are shown in Figures 7 and 8.

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GENERAL DISCUSSION Over the past decade, the interest in using amorphous drug dispersions to enhance the solubility of poorly soluble drugs has increased dramatically.36 Amorphous drug forms possess shortrange order and require a lower energy input to achieve aqueous dissolution. Furthermore, because amorphous drugs exhibit high levels of supersaturation in aqueous media, a higher apparent solubility may be realized. In contrast to the crystalline form, the amorphous form of a drug is thermodynamically unstable and may recrystallize during storage and/or dissolution.37 Therefore, one of the foremost challenges in developing amorphous drug dispersions is to inhibit crystallization, particularly during storage. Moreover, one key aspect is being able to determine the likelihood for recrystallization and developing platforms that can inhibit such transformations. In 244

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Figure 7. HyperDSC thermograms of HPMCAS-FD and Soluplus-FD solid dispersions (annealed for 24 h) containing varying FD weight percentages: (1) 36% FD-Soluplus, (2) 25% FD-HPMCAS, (3) 55% FD-Soluplus, (4) 44% FD-HPMCAS, (5) 72% FD-Soluplus, (6) 64% FDHPMCAS, and (7) 100% FD.

Metastability plays a significant role in polymer phase transitions, which has been proven theoretically and experimentally.42,45 Similar to polymer−polymer liquid mixtures, drug−polymer amorphous (liquid) mixtures can also be supercooled well below the equilibrium temperature (defined composition) and thus have no crystalline content. In this system, with consideration of the Gibb's free energy of mixing, there is the potential for specific drug−polymer compositions to decompose into coexisting amorphous (liquid) phases rather than transform directly into lower energy crystal state (crystallization). Hence, amorphous−amorphous (liquid− liquid) phase separation may precede crystallization. In this metastable region, an appropriately formulated system can provide a sufficiently high kinetic barrier and thus prevent phase separation. At drug compositions within the metastable zone, drug is supersaturated in the polymeric carrier; however, supersaturation may be maintained by the apparent miscibility of the components in the amorphous state, particularly if the storage temperature is below the Tg of the drug−polymer system (Figure 9, zone D). Above the Tg, molecular mobility is high, and the system may achieve equilibrium quite quickly; below this temperature, the metastable system falls into a “frozen” state characterized by low molecular mobility and long relaxation times, characteristic of glassy structures. Consequently, in this state, the miscibility is an apparent value,27 which suggests that a supersaturated amorphous drug−polymer solid dispersion mixture (zone D) may remain crystal-free over pharmaceutically relevant time scales, if engineered appropriately. This is an interesting and particularly useful consideration

light of the above, drug is often embedded in a solid polymeric matrix as a solid dispersion to produce an amorphous mixture of drug and the polymer (often observed as a single Tg). These drug−polymer platforms may therefore offer improved solubility while also increasing stability. In such systems, defining drug−polymer miscibility and the maximum drug solubility within the chosen carrier is of paramount importance to maintain long-term stability.38,39 In this article, we report a small-scale experimental method that is very useful in defining the miscibility and solubility of a model poorly soluble drug (FD) in two model polymeric carriers, namely, HPMCAS-HF and Soluplus. Applying a combination of DSC and F−H interaction theory, we have constructed phase diagrams for both systems. Importantly, the phase diagram clearly identifies the phase boundaries of the system. As shown in Figure 9, above the liquid−solid boundary (zones A and B), drug−polymer mixtures are expected to remain stable with respect to infinitesimal fluctuations within the system. The predicted equilibrium solubility of drug within both polymeric carriers is relatively low. This liquid−solid phase boundary has been determined from melting point depression experiments, in which the melting point of the crystalline drug drops to lower temperatures, due to interactions between drug and amorphous polymer.20,40 Below the liquid−solid phase boundary (lower temperature), a metastable zone exists (Figure 9, zones C and D), representing a metastable state.41,42 Phase separation (physical decomposition) within this zone not only requires activation energy input but also needs to overcome kinetic effects. 245

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Figure 8. Expansion of the glass transition region from HyperDSC thermograms shown in Figure 7: (1) 36% FD-Soluplus, (2) 25% FD-HPMCAS, (3) 55% FD-Soluplus, (4) 44% FD-HPMCAS, (5) 72% FD-Soluplus, and (6) 64% FD-HPMCAS.

composition at which the Gibb's free energy curve cuts the xaxis. By contrast, decomposition in the unstable state (zones E and F from Figure 9) will be more favorable.10

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CONCLUSION

This study has established a small-scale thermal method that can be used in combination with F−H interaction theory to predict the physical stability of amorphous drug solid dispersions. The temperature dependence of χ was successfully determined for both HPMCAS−FD and Soluplus−FD systems. Phase diagrams of temperature−composition and free energy of mixing (ΔGmix) were constructed, and it was noted that the interaction parameters of HPMCAS−FD and Soluplus−FD calculated using the melting point depression method were comparable to those calculated using van Krevelen's solubility parameter method. The relative rank of the interaction parameters was consistent, regardless of the method used in their calculation. The solubility and miscibility of FD in Soluplus were higher than in HPMCAS. The constructed phase diagrams were assessed above the glass transition temperature of the amorphous solid dispersion system. The results clearly identified a metastable and unstable concentration for each system. Given the increasing interest over the last 5 years in using melt extrusion to produce amorphous dispersions, the construction of drug composition−temperature phase diagrams allows one to readily identify a temperature/drug load space in which it becomes possible to engineer stable solid dispersions.

Figure 9. Phase diagram of a model drug−polymer binary system based on F−H theory.

for formulations containing amorphous drugs.43 Local stability of binary drug−polymer systems containing drug as a “solute” and polymeric carrier as a “solvent” is possible within a defined composition and temperature range. As shown in Figure 5a,b, the drug composition at which the free energy of the system becomes positive is dependent upon the temperature and the polymeric matrix being used. Undoubtedly, polymers that are capable of offering complementary hydrogen-bonding sites to the drug will provide greater resistance to crystallization.44 An increased stability would be expected at the point when ΔGmix is at a minimum, that is, drug compositions lower than the drug 246

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AUTHOR INFORMATION

Corresponding Author

*Address: Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom. Tel: +44(0)28 9097 2646. Fax: +44(0)289024 7794. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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