Effect of Organic Acids on Molecular Mobility, Physical Stability, and

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Effect of organic acids on molecular mobility, physical stability and dissolution of ternary ketoconazole spray dried dispersions Michelle H. Fung, and Raj Suryanarayanan Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00593 • Publication Date (Web): 25 Oct 2018 Downloaded from http://pubs.acs.org on October 27, 2018

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Molecular Pharmaceutics

Effect of organic acids on molecular mobility, physical stability and dissolution of ternary ketoconazole spray dried dispersions Michelle H. Fung1, Raj Suryanarayanan1* 1Department

of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA *Corresponding Author: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States. Phone: 612-624-9626. Fax: 612-6262125. E-mail: [email protected]

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract In an earlier investigation, ketoconazole (KTZ) - organic acid

coamorphous systems

were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung et al, Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining supersaturation and drug precipitation was observed.

Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were

prepared with ketoconazole, polyvinylpyrrolidone (PVP) and each oxalic (OXA), tartaric (TAR), citric (CIT) or succinic (SUC) acid. When compared with amorphous KTZ, solid dispersions of KTZ-PVP exhibited a moderate reduction in molecular mobility and small improvement in dissolution performance. The incorporation of acid (OXA, TAR or CIT) in PVP-KTZ solid dispersion led to orders of magnitude increase in α-relaxation times and decrease the crystallization propensity.

These ternary ASDs were stable while

crystallization of cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.

Keywords: Amorphous solid dispersions, dissolution, crystallization, physical stability, molecular mobility, coamorphous



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Introduction While amorphization can lead to an increase in the apparent solubility of active pharmaceutical ingredients (APIs), physical instability leading to crystallization can occur during drug product manufacture and storage1-3. The conventional stabilization strategy is to prepare amorphous solid dispersions (ASD) where an API is molecularly mixed with a polymer 4-7. While there are several approaches for polymer selection, from a practical perspective, only a small number of polymers have been used to prepare ASD formulations8. Moreover, in commercial formulations, the polymer is generally used at a high concentration – a strategy practically unattractive for high dose drugs. In such cases, other additives have been explored, for enhancing the stability and dissolution performance of amorphous APIs9. Small molecule excipients are often added to facilitate processing or to enhance dissolution6, 10-11. Moreover, APIs which are weak acids or bases exhibit pH dependent solubility. As a result, addition of acidic or basic small molecule excipients to drugpolymer ASDs can lead to an increase in dissolution rate. For example, the addition of orthophosphate/citric acid buffer to furosemide-PVP ASD modulated the dissolution behavior of furosemide12-13. More recently, incorporation of sodium carbonate to an ASD of telmisartan (in PVP), a weakly acidic API, showed a 3-fold improvement in dissolution rate relative to the API alone14. Likewise, inclusion of fumaric acid, an acidic excipient, increased the dissolution rate of an ASD of a weakly basic API, isradipine (also in PVP)15. Formation of ternary drug-polymer-additive (small molecule excipient) ASDs can potentially improve the overall solid-state physical stability of the system. For example, ASDs containing meglumine, indomethacin and PVP were shown to be more physically


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stable relative to a binary dispersion containing only the drug and polymer16.

The

increased stability was attributed to acid-base interactions between indomethacin and meglumine. In another case, miscible dispersions could be readily prepared using PVP, citric acid and indomethacin while indomethacin exhibited only limited miscibility with citric acid17. Miscibility of the components is necessary for the formation of stable ASDs18. On the other hand, since small molecule excipients generally have low glass transition temperatures, their incorporation can plasticize drug-polymer ASDs and thereby accelerate drug crystallization.

For example, addition of glycerol increased the

crystallization propensity of celecoxib-PVP ASDs, an effect attributed to increase in molecular mobility19. Surfactants incorporated in ASDs for improving wetting during dissolution, can also increase the growth rate of the API crystals20. Many organic acids (oxalic, tartaric, citric) effectively stabilized ketoconazole (KTZ), a weak base, in the amorphous state21. Each acid interacted with KTZ, either ionically, or by hydrogen bonding. As the strength of the KTZ-acid interaction increased, the reduction in molecular mobility was more pronounced.

When two systems prepared with

structurally similar dicarboxylic acids (oxalic and succinic acids) were compared, the increase in physical stability could be explained by reduction in mobility. However, two of the systems were exceptionally stable (KTZ-tartaric and KTZ-citric) indicating that in addition to mobility, the intrinsic crystallization propensity of the KTZ-acid complex (salt or cocrystal) warrants consideration.

As the strength of the acid increased, the

enhancement in dissolution of the coamorphous system became more pronounced. However, when placed in contact with the dissolution medium (water), while KTZ-citric



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and KTZ-tartaric systems resisted crystallization, KTZ-succinic cocrystal and KTZ-oxalic salt readily crystallized. The overall goal of this project is to incorporate a small molecule excipient to improve the performance of a drug-polymer ASD. Polyvinylpyrrolidone (PVP), in light of its popularity, was chosen as the model polymer. However its ability to stabilize KTZ was limited, an effect explained by the lack of any specific drug-polymer interaction.22 Incorporation of an organic acid, even at a modest concentration, is expected to improve the solid-state stability as well as the dissolution performance of the KTZ-PVP ASD. We hypothesize that the interactions between KTZ and each acid, observed in the coamorphous binary systems, will persist in the ternary drug-polymer-acid ASDs. The organic acids (oxalic, tartaric, citric and succinic acids) were selected based on their strengths (pKa values) and the effect of each acid on the molecular mobility of the ternary ASDs will be determined by dielectric spectroscopy (DES). While FTIR will be used to assess the interactions between the components in the ternary systems, crystallization propensity of KTZ in the ASDs will be examined using differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Finally, the dissolution performance of the ternary ASDs will be evaluated. Such an approach will reveal the e synergistic effects of the excipients, if any, on both stabilization and dissolution performance.


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EXPERIMENTAL Materials. Ketoconazole (KTZ) was donated by Laborate Pharmaceuticals (Haryana, India). Oxalic acid, citric acid anhydrous, D, L-tartaric acid, succinic acid (all from SigmaAldrich, Missouri, USA) and polyvinylpyrrolidone (PVP K12; BASF, New Jersey, USA) were used as received. Preparation of amorphous systems. The ketoconazole amorphous solid dispersions (ASDs) contained PVP and one of the following organic acids: oxalic, tartaric, citric or succinic acid. The drug to polymer ratio was 9:1 w/w and the drug to acid molar ratio was 1:1. A methanolic solution containing KTZ (5% w/v total solid content), PVP and each acid was fed to the spray dryer (B-290 Buchi, Delaware, USA) at 3.5 ml/ min. The inlet and outlet temperatures were maintained at ~55 ºC and ~35 ºC respectively. To minimize the residual solvent content, the spray dried samples were dried under vacuum for 20 hours (RT). The preparation of ketoconazole coamorphous systems with each acid are described in an earlier investigation23. Differential Scanning Calorimetry (DSC). The experimental details were provided in our earlier publication21. Powder dissolution.

The experimental details including data analyses (the

determination of the area under the curve) were presented earlier21. Scanning Electron Microscopy (SEM).

The powder samples

were sprinkled on

aluminum stubs with a double-sided carbon tape, coated with platinum (20 Å), and imaged pe (Jeol 6500 F microscope, Hitachi, Japan). Powder X-ray diffractometry (PXRD). A powder X-ray diffractometer (D8 ADVANCE, Bruker AXS, WI, USA) fitted with a variable temperature stage (TTK 450; Anton Paar,



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Graz-Straβgang, Austria) and a Si strip one-dimensional detector (LynxEye) was used.XRD patterns were collected using Cu Kα radiation (1.54 Å; 40 kV x 40 mA), over the angular range of 5 - 35° 2θ with a step size of 0.02° and a dwell time of 0.5 s. Fourier Transform Infrared Spectroscopy (FT-IR). Spectra, over the range of 3500 800 cm-1, were obtained at RT (Bruker Vertex 80 spectrometer, MA, USA). Sixty-four scans were obtained, at a resolution of 4 cm-1. Dielectric Spectroscopy (DES). A dielectric spectrometer (Novocontrol Alpha-AK high performance frequency analyzer, Novocontrol Technologies, Germany) equipped with a temperature controller (Novocool Cryosystem) was used, over the temperature range of 25 to 120 °C. Each experiment was carried out, in the frequency range of 10-2 to 106 Hz, at a fixed temperature.

ASD powder was confined by a PTFE spacer and (1 mm

thickness, 59.69 mm2 area and 1.036 pF capacitance) between two gold-pated copper electrodes (20 mm diameter).


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Results and discussions Selection of model systems Ketoconazole (KTZ) is a weak base with two pKa values (pKa1=6.5 and pKa2= 2.9)24. Organic acids (oxalic, tartaric, citric and succinic acids) of different strengths, ranging in pKa values from 1.3 to 4.2 were selected. We had reported that each of the acids interacted ionically and/or hydrogen bonded with KTZ

in coamorphous systems23.

Polyvinylpyrrolidone (PVP) was selected since it does not strongly interact with KTZ22. The chemical structures of KTZ, the acids and PVP are shown in Figure 1.

Figure 1. Chemical structures of (a) ketoconazole, (b) succinic acid, (c) citric acid, (d) tartaric acid, (e) oxalic acid and (f) polyvinylpyrrolidone.



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Baseline characterization of ternary ASDs We had earlier prepared KTZ – organic acid coamorphous systems by spray drying and observed them to be X-ray amorphous23. Spray dried KTZ-PVP and their ASDs with each citric (CIT), tartaric (TAR), oxalic (OXA) and succinic acids (SUC) were also X-ray amorphous. The ASDs exhibited a broad halo over the angular range of 5 to 35 °2θ (Figure 2). The scanning electron micrographs of the spray dried powders are provided in the Supporting Information (Figure S1).

Figure 2. Representative XRD patterns of spray dried samples immediately after preparation.


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Molecular mobility Using dielectric spectroscopy (DES), the α-relaxation times (𝜏𝛼) of KTZ were determined as a function of temperature (Figure 3). Addition of PVP (10% w/w) caused a modest but measurable increase in relaxation times. The incorporation of TAR in PVP-KTZ ASD resulted in the most pronounced reduction in molecular mobility, reflected by the long relaxation times. The effect was observed over the entire investigated temperature range. The effects of CIT and OXA were comparable and resulted in ≥ 2 orders of magnitude increase in α-relaxation times when compared to KTZ-PVP.

On the other hand, the

mobility of KTZ-PVP-SUC ASD was similar to that of KTZ-PVP. The Vogel-Fulcher-Tamman (VFT) equation was used to estimate the fragility of the ASDs25.

The calculated Kauzmann temperature (T0), strength parameter (D) and

dielectric Tg values are provided in Supporting Information (Table S1). Much like the KTZacid coamorphous systems, the ternary ASDs were fragile, with D-values between 6.0 and 10.9.

For many systems, the dielectric Tg values were different from the calorimetric

Tg (discussed later; Table 1).



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Figure 3. Temperature dependence of α-relaxation times of (a) amorphous KTZ, (b) KTZ-PVP ASD, KTZ-PVP ASDs with (c) oxalic, (d) succinic, (e) citric and (f) tartaric acid. (Mean ± SD; n=3)

Each ternary system was compared with the binary KTZ-PVP ASD as well as the corresponding KTZ-acid coamorphous systems (Figure 4).

This enabled us to

comprehensively evaluate and compare the effects of each acid, alone and in combination with PVP. While The α-relaxation time of KTZ-PVP-CIT was nearly 2 orders of magnitude longer than that of coamorphous KTZ-CIT (Figure 4a). In case of the OXA and TAR systems, the mobility of the ternary ASDs was similar to that of the corresponding KTZ-acid systems (Figure 4b and d). KTZ-PVP-SUC, however, exhibited similar mobility to PVP-KTZ as well as KTZ-SUC (Figure 4c). This was the only case where the two binary mixtures and the ternary system exhibited similar mobility behavior, particularly at the higher temperatures. To understand the differences in mobility of the ternary systems, the molecular interactions between the components were evaluated. 12 ACS Paragon Plus Environment

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Figure 4. Temperature dependence of α-relaxation times of PVP-KTZ ASD with PVPacid and PVP-KTZ-acid coamorphous systems. The acids were: (a) citric, (b) tartaric, (c) succinic and (d) oxalic (Mean ± SD; n=3).

Molecular interactions The IR spectrum of PVP-KTZ ASD exhibited an absorption band at 1680 cm-1 attributable to the carbonyl stretching of the pyrrolidone group in PVP (not shown). In the ternary ASDs containing KTZ, PVP and OXA, a broad absorption band was observed between 1645 and 1587 cm-1 (Figure 5a; highlighted region). An absorption in the same region observed in coamorphous KTZ-OXA was attributed to the ionic interactions between KTZ and the acid26.

This suggested that the drug-acid interactions observed in the

coamorphous system persisted in the ternary dispersion.

In KTZ-PVP-TAR, the 13

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absorption between 1645 and 1587 cm-1 was attributed to the ionization of tartaric acid (Figure 5b). The IR spectrum resembled that of coamorphous KTZ-TAR. Similarly, in KTZ-PVP-CIT, ionization of citric acid can explain the broad absorption band between 1645 and 1587 cm-1 (Figure 5c). Finally, the IR spectrum of KTZ-PVP-SUC suggested that KTZ (amide carbonyl) was hydrogen bonded to

succinic acid (Figure 5d).

In

summary, in the ternary ASDs, the addition of PVP did not alter the molecular interaction between KTZ and each acid.

Figure 5. FTIR spectra of KTZ-PVP ASDs with (a) oxalic acid, (b) tartaric acid, (c) citric acid and (d) succinic acid. The appearance of the absorption band (highlighted in purple) between 1645 and 1587 cm-1 is attributed to the interactions between KTZ and the acids.


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Thermal analysis The DSC heating curve of PVP-KTZ ASD revealed a glass transition (Tg) at 49.6 (± 0.4) ºC, followed by crystallization at 110.2 (± 0.5) ºC (Tc) and melting at 147.0 ± 0.2 ºC (Tm) (Figure 6; values are reported in Table 1). The Tg value is in good agreement with literature reports22, 27. The incorporation of tartaric or citric acid in PVP-KTZ ASD resulted in a Tg increase.

The Tg values of the ternary ASDs were similar to that of the

corresponding KTZ-acid coamorphous systems (Table 1). Moreover, the addition of either citric or tartaric acid to KTZ-PVP decreased the overall crystallization propensity of the ASDs. Neither system exhibited crystallization when heated up to 175 ºC (Figure 6). On the other hand, while the addition of oxalic acid to PVP-KTZ ASD caused a pronounced Tg increase (Table 1), crystallization was observed during heating. The melting temperature of the crystallized phase (193.8 ± 0.3 ºC) suggested the formation of KTZ-OXA salt28. The Tg of KTZ-PVP-SUC was 47.4 ºC, slightly higher than that of KTZPVP. While the crystallization temperature (Tc) was about 10 degrees less than that observed in KTZ-PVP, the value was close to that of coamorphous KTZ-SUC (Table 1). The melting temperature of the crystallized phase, 162.1 ± 0.1 ºC, was in excellent agreement with the reported Tm value for KTZ-SUC 1:1 cocrystal28. Thermal analysis suggested that the incorporation of organic acid influenced the solid-state properties of the ASD while PVP, even at 10% w/w, had minimal effects on stability.



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Figure 6. Representative DSC heating curves of ternary KTZ-PVP ASDs with each: (a) oxalic acid, (b) tartaric acid, (c), citric acid and (d) succinic acid, and (e) binary PVP-KTZ ASD. (n=3)

Table 1. DSC characterizations of KTZ-PVP ASDs with each oxalic, tartaric, citric and succinic acid. System Tg, °C Tc, °C Tm, °C KTZ 43.3 ± 0.8 109.3 ± 0.4 147.9 ± 0.2 KTZ-PVP 49.6 ± 0.4 110.2 ± 0.5 146.7 ± 0.3 KTZ-OXA 66.2 ± 1.4 125.8 ± 2.6 198.2 ± 1.8 KTZ-PVP-OXA 65.9 ± 0.4 122.4 ± 0.4 193.8 ± 0.3 KTZ-TAR 66.4 ± 0.3 NA* NA KTZ-PVP-TAR 67.3 ± 0.3 NA NA KTZ-CIT 59.5 ± 0.6 NA NA KTZ-PVP-CIT 61.1 ± 0.3 NA NA KTZ-SUC 43.6 ± 0.5 100.1 ± 2.2 164.1 ± 0.3 KTZ-PVP-SUC 47.4 ± 0.1 98.6 ± 0.1 162.1 ± 0.1 *NA – not applicable. (Mean ± SD; n=3)


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Isothermal crystallization To assess the solid-state physical stability, the ternary ASDs were stored at an elevated temperature of 75°C (~0% RH). After storage for 7 days, XRD revealed pronounced KTZ crystallization in PVP-KTZ ASD (Figure 7). In case of PVP-KTZ-SUC, the crystallizing phase was KTZ-SUC cocrystal. ASDs containing OXA, TAR or CIT, on the other hand, remained amorphous. Thus, the incorporation of carboxylic acids to drug-polymer ASD can lead to a change in the crystallizing phase and consequently alter the physical stability of the system.

Figure 7. Representative powder XRD patterns of KTZ-PVP ASDs after storage for 7 days at 75 °C. Dissolution The dissolution profiles of KTZ, KTZ-PVP and KTZ-PVP-acid ternary ASDs are presented in Figure 8 and the results are summarized in Table 2. The area under the curve (AUC) values obtained from the concentration-time profiles provides an avenue to compare their dissolution performance (Table 2). PVP is known to function as a crystallization inhibitor. However, the addition of PVP, at 10% w/w, only slightly enhanced the dissolution of KTZ 17 ACS Paragon Plus Environment


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(Figure 8; Table 2). Thus, the conventional approach of incorporating the drug in a polymer offered only marginal dissolution enhancement. It is recognized that the PVP concentration was low (10% w/w). On the other hand, the addition of an organic acid (1:1 KTZ-acid molar ratio) to the PVP-KTZ dispersion dramatically enhanced the dissolution performance of KTZ.

Among the four acids tested, the largest AUC increase was

observed in the OXA system, with ~5-fold increase relative to KTZ-PVP binary ASD. The impact of the acids could be rank ordered as: OXA > CIT > TAR > SUC. In KTZ-acid coamorphous systems, the enhancement in dissolution can be rank ordered as: OXA > TAR ≈ CIT > SUC (Table 2). The acid, by decreasing the diffusion layer pH around the dissolving solid, enhanced KTZ solubility. Thus the effect appeared to become more pronounced as the strength of the acid increased.21 In both KTZ-PVP-TAR and KTZ-PVP-OXA systems, a pronounced fraction of the KTZ (~85%) went into solution (Cmax in Table 2; Figure 8). In these systems, the excipients facilitated very rapid dissolution of a substantial fraction of the drug. As a next step, when the ternary ASDs and the corresponding coamorphous (KTZ-acid) systems were compared, the ternary ASDs exhibited superior dissolution performance (higher AUC values) though the effect was small (Figure 9; Table 2). Interestingly, the dissolution profile of each ternary system was similar to that of its corresponding coamorphous system. In the KTZ-acid systems, a sharp rise in the KTZ concentration (as was observed in all cases except with SUC), was followed by a pronounced decrease in its concentration over time (Figure 9). The addition of polymer had a small but measurable effect in delaying drug crystallization from solution.

The overall increase in dissolution

performance of the ternary ASDs could be attributed to the effect of the acids.


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The particle size and morphology of the ternary ASDs were examined using SEM (Supporting information, Figure S1). In case of KTZ-PVP, the addition of 10% w/w PVP yielded dispersion with Tg of 49.6 ± 0.4. In the spray dryer, these particles can be expected to be in supercooled (rubbery) state when they traverse the outlet (Toutlet =35 ºC) due to the expected pronounced Tg lowering by the sorbed solvent (methanol). As a result, the PVP-KTZ ASD particles appear to agglomerate before they are completely formed.

Incorporation of SUC in PVP-KTZ ASD was ineffective in decreasing the

molecular mobility of the system. This is one possible explanation for the large size of PVP-KTZ and PVP-KTZ-SUC (spray-dried powders) particles.

In contrast, the

incorporation of CIT, OXA or TAR led to a pronounced reduction in molecular mobility of the systems. When entering the spray dryer cyclone, these systems are likely to be in the glassy state with a low molecular mobility. The SEM images showed that these particles were small and spherical (Supporting information, S1). The rapid dissolution observed in the CIT, OXA and TAR systems could be explained at least partially, by the consequent high surface area of the spray dried particles. Moreover, the particle size and morphology of the ternary systems are similar to that of the coamorphous systems (Supporting information, Figure S2).



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Figure 8. Dissolution profiles of PVP-KTZ and its ASD with each acid. KTZ concentrations were determined using HPLC. (Mean ± SD; n=3)


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Figure 9. Comparing PVP-KTZ and its ASD with each acid. (Mean ± SD; n=3)



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Table 2. Dissolution results of crystalline KTZ, amorphous KTZ, coamorphous KTZ-acid systems, KTZ-PVP, and KTZ-PVP with each acid. 2AUC Tmax Cmax (µg/mL) AUC(0→t) (µg/mL*min) 1AUC ratio ratio (min) (Mean ± SEM) min*µg/mL crystalline KTZ 180 5.7 ± 0.3 855.2 ± 20.7 1.0 amorphous KTZ 120 12.7 ± 1.0 1714.1 ± 72.1 2.0 1.0 KTZ-PVP 60 12.8 ± 1.4 1989.0 ± 117.5 2.3 KTZ-SUC 15 28.1 ± 0.9 4005.8 ± 57.4 4.7 2.8 KTZ-PVP-SUC 60 36.0 ± 1.7 5600.2 ± 127.0 6.5 KTZ-CIT 10 63.4 ± 0.5 5671.8 ± 61.3 6.6 KTZ-TAR 5 84.3 ± 1.1 5677.2 ± 166.2 6.6 3.2 KTZ-PVP-TAR 5 87.4 ± 1.3 6455.9 ± 323.7 7.5 3.9 KTZ-PVP-CIT 15 69.1 ± 1.0 7680.8 ± 189.9 9.0 KTZ-OXA 10 84.7 ± 4.9 8040.3 ± 399.1 9.4 4.9 KTZ-PVP-OXA 30 83.7 ± 3.2 9768.5 ± 298.4 11.4 1 (AUC (0→t) of sample)/ (AUC(0→t)) of crystalline KTZ. 2 (AUC (0→t) of sample)/ (AUC(0→t)) of PVP-KTZ. SEM = standard error of the mean.

Discussion The property a KTZ-PVP ASD could be modulated by the addition of an organic acid. The incorporation of CIT, TAR or OXA to KTZ-PVP ASD resulted in a pronounced reduction in molecular mobility reflected by the ≥ 2 orders of magnitude increase in αrelaxation times when compared to KTZ-PVP (Figure 4). The ionic interaction between KTZ and each acid, evident from IR spectroscopy, could explain the increase in relaxation times (Figure 5). This decrease in mobility may be partially responsible for the pronounced physical stability of these systems. All the three KTZ-PVP-acid systems resisted crystallization, both when heated in the DSC (Figure 6; Table 1) and when stored at 75 °C for one week (Figure 7). In contrast, in the KTZ-PVP-SUC system, spectroscopy suggested hydrogen bonding interaction between KTZ (amide carbonyl) and succinic acid (Figure 5d). There was not a pronounced difference in the relaxation times of the KTZ22 ACS Paragon Plus Environment

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PVP and KTZ-PVP-SUC systems (Figure 4c). Heating this ternary system resulted in the formation of KTZ-SUC 1:1 cocrystal (Figures 6 and 7). This system exhibited less resistance to crystallization than the ternary dispersions prepared with the other acids. In an earlier investigation, we had compared the dissolution behavior of KTZ-acid coamorphous systems.21

The dissolution enhancement was observed to be more

pronounced as the strength of the acid (OXA > TAR > CIT > SUC) increased.

Significance As the number of poorly water-soluble development compounds increases, the development of formulation strategies for enhancing the apparent solubility of APIs becomes increasingly important.

Salt formation can offer desirable physical and

chemical properties, while amorphization has the potential to significantly improve the apparent solubility of the APIs. The water solubility of APIs, which are weak acids or bases, can be highly pH dependent. For example, the solubility of a weakly basic drug, KTZ, increases dramatically when the pH is < 4.24

As suggested by an earlier

investigation, the incorporation of acids decreased diffusion layer pH during dissolution of the coamorphous systems which resulted in dissolution enhancement.21 The acids, however, were ineffective in maintaining supersaturation. Drug-polymer-acid ASDs take advantage of the solubility enhancement brought about by the counterion (or coformer) as well as the stabilization effects of the polymer. Hence, ternary ASDs exploit the solubility advantage of both salt (or cocrystal) formation and amorphization.

Conclusions



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Addition of an organic acid (OXA, CIT or TAR) to PVP-KTZ amorphous solid dispersion, (i) decreased the crystallization propensity of KTZ and (ii) improved the dissolution performance of KTZ. . ASSOCIATED CONTENT SUPPORTING INFORMATION Figures containing the particle size and morphology of the ASDs examined using scanning electron microscopy.

A table presenting the VFT fitted parameters of

coamorphous KTZ-acid and KTZ-PVP-acid ternary ASDs. AUTHOR INFORMATION Corresponding Author *Address: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States. E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS M. H. Fung was partially supported by PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship from University of Minnesota. This project was partially funded by the William and Mildred Peters Endowment Fund. Powder XRD work 24 ACS Paragon Plus Environment

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was carried out at the Characterization Facility at University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org).

We thank

Upsher-Smith Laboratories (Drs. Limin Shi and Howard Chen) for providing access to spray drying equipment.

We thank Kārlis Bērziņš, Jiangnan Dun, Janice Laramy,

Michaela Roslawski and Wei-Jhe Sun for their help.



Page 26 of 27

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