Novel Supercritical Carbon Dioxide Impregnation Technique for the

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A Novel Supercritical Carbon Dioxide Impregnation Technique for the Production of Amorphous Solid Drug Dispersions: A Comparison to Hot Melt Extrusion. Catherine Potter, Yiwei Tian, Gavin Walker, Colin McCoy, Peter Hornsby, Conor Donnelly, David S. Jones, and Gavin P. Andrews Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp500644h • Publication Date (Web): 02 Mar 2015 Downloaded from http://pubs.acs.org on March 11, 2015

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Molecular Pharmaceutics

A Novel Supercritical Carbon Dioxide Impregnation Technique for the Production of Amorphous Solid Drug Dispersions: A Comparison to Hot Melt Extrusion.

Catherine Potterab, Yiwei Tiana, Gavin Walkerc, Colin McCoya Peter Hornsbyb, Conor Donnellya, David S. Jonesa, and Gavin P. Andrewsa* a

The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre,

Queen’s University, 97 Lisburn Road, Belfast. BT9 7BL, Northern Ireland, UK. b

School of Mechanical and Aeronautical Engineering, Queen’s University, 97 Lisburn Road,

Belfast. BT9 7BL, Northern Ireland, UK c. Department of Chemical and Environmental Science, University of Limerick, Ireland.

*Correspondence to: Gavin P. Andrews Tel: +44 (0) 28 9097 2646; Fax: +44 (0) 28 9024 7794; E-mail: [email protected]

Keywords: Supercritical Fluid Impregnation, Hot Melt Extrusion, Solid Dispersions, Soluplus, PVP.

ACS Paragon Plus Environment


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Abstract The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages in respect of improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, whilst the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, Indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterisation of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus® and Polyvinylpyrrolidone K15 using both SFI and HME and characterised for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers formulations containing 50% w/w INM, manufactured via SFI, contained drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method, however for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained and for all systems SFI formulations performed better than similar HME formulations.


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Introduction The low aqueous solubility of many new chemical entities is a major issue currently being faced by the pharmaceutical industry with recent estimates suggesting that 90% of drugs within pharmaceutical pipelines possess limited aqueous solubility. It is also approximated that 40% of marketed oral drug products are considered as practically insoluble ( SOL HME. The disparity between supersaturation concentrations reached for the two polymers is attributed to the greater hydrophilicity of PVP over Soluplus and reflects similar results from Guo et al. (2013) who observed a slower carrier-controlled dissolution from a DiflusinalSoluplus formulation than from Diflusinal-PVP [32]. The drug release curves observed in this work (Figure 10) do not exhibit the spring and parachute shape and instead display a continuous increase in drug concentration over the full time of dissolution. It was also observed that none of the formulations dissolved completely over the course of the dissolution. It is assumed that neither the drug nor the polymer dissolve completely over eight hours in acidic conditions. It has been observed that the shape of the dissolution curve and drug concentration measured can be highly dependent on the method of measuring the dissolved drug [44]. Alonzo et al. (2011) observed very different dissolution profiles by first using an in situ UV-



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Vis method and subsequently by encasing the UV probe in a dialysis membrane. The much higher apparent readings gathered without the dialysis membrane in place were attributed to interference from drug molecules contained in polymeric nanoparticles rather than those truly dissolved in the dissolution medium. With the dialysis membrane in place the initial rate and extent of drug dissolution measured was greatly reduced and the dissolution behaviour was broadly linear. A number of the dissolution profiles gained in this work were also linear so to provide a more quantitative analysis linear regression analysis was carried out. The dissolution profiles of all formulations showed a good correlation to a linear fit except for 10 PVP SFI and 50 PVP SFI (Table 7) which exhibited an initial burst release. While all PVP formulations attained similar final concentrations after 8 hours, the higher initial release rate meant that these were also the formulations with the greatest AUC8hr value. The higher rate of release of drug from the SFI formulations was attributed to surface area differences which enabled faster dissolution of the polymer and is in agreement with the typically porous nature of supercritical fluid processed products [20]. It also contributes to the hypothesis that the dissolution from these formulations was carrier controlled. The 50 SFI formulations, which contained some crystalline material showed better dissolution than some of the completely amorphous lower drug loadings. This is in agreement with Pina et al. (2014) who showed that for formulations with similar drug but different crystalline content, the completely amorphous formulation did not always show the best dissolution [50] with dissolution performance being attributed to the polymer rather than the morphology of the API.

Amorphous stability studies The ten completely amorphous formulations were subjected to conditions of 40 ⁰C and 75 %RH for four months, after which the presence of crystalline content was investigated using HyperDSC. Raman spectroscopy was not a suitable characterisation technique for this study as the annealed samples exhibited Raman fluorescence. HyperDSC traces for the Soluplus formulations are illustrated in Figure 12. A Tg is apparent around 30-90 ⁰C and, if present, the INM endotherm appears in the area bounded by dotted lines. The enthalpy associated with the endotherms gained for each formulation are summarised in Table 8. 10 SOL SFI remained completely amorphous while the average crystalline content found in 10 SOL HME measured an enthalpy 0.09 J/g. One of the 10 SOL HME replicates was completely amorphous so crystallinity was not uniformly dispersed throughout the


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formulation. All other formulations showed some degree of crystallinity. Considering the 10 and 30% w/w loaded formulations, a two way ANOVA showed statistically significant differences between drug loading but not between processing methods. Therefore it can be concluded that Soluplus formulations produced using SFI show a similar stability to those produced using hot melt extrusion. This is in agreement with the parity of strength of interactions indicated by FTIR in both SOL HME and SOL SFI formulations. A two way ANOVA confirmed statistical differences in the means of melting enthalpies of PVP formulations on both a drug loading and processing method basis. As indicated in Table 8, a larger endotherm was observed for SFI formulations in comparison to similar HME formulations. A difference in processing methods was not shown by Soluplus formulations and this disparity in behaviour is attributed to the hydrophilicity of PVP. PVP is an extremely hydrophilic powder and becomes tacky after exposure to room temperature and humidity. Formulations were pressed into a disk prior to the stability study and while the Soluplus formulations maintained their structural integrity, similar PVP formulations became more fluid and flowed to take the shape of their container. The relative instability is therefore attributed to the greater mobility induced by the uptake of water by the more hydrophilic polymer rather than to thermodynamic factors. The greater degree of crystallisation which occurred in PVP SFI formulations in particular is attributed to the greater surface area of SFI formulations which initially allowed a greater rate of intake of moisture. It is also in agreement with FTIR studies which suggested that relatively stronger interactions were generated through processing using HME than using SFI. Sinclair et al. (2011) [52] acknowledge the significant effect of increasing humidity on the amorphous stability of an amorphous solid dispersion of ibipinabant formulated using PVP, noting that moisture had a significant impact on the amorphous stability of the API.



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Conclusion Amorphous solid dispersions of INM with PVP and Soluplus have been successfully produced using HME and SFI. While treatment of γ-INM with scCO2 did not produce the amorphous form of the API, a morphology change was observed on the introduction of polymeric excipients Soluplus and PVP into the reaction chamber. While relatively higher amorphous drug loadings could be incorporated using HME the temperatures required were up to 100 ⁰C higher than for SFI. For INM-PVP the increased temperatures appeared to generate greater interaction between the species with FTIR showing more hydrogen bonding for HME formulations than SFI. Of the completely amorphous formulations a greater homogeneity was shown by extruded formulations over those produced using supercritical fluids highlighting the relative difficulty associated with processing using supercritical fluids and high viscosity polymers without the use of surfactants. PVP formulations showed a higher dissolution rate and final concentration than Soluplus formulations, the former producing a 4-4.5 times enhancement of crystalline solubility in comparison to two times for Soluplus. The difference between the two sets of carrierdependent dissolutions was attributed to the difference in dissolution rate of each polymer, PVP being more hydrophilic and being of a smaller molecular weight. Using Soluplus as the stabilising excipient, no difference in processing method was found for amorphous stability, SFI formulations exhibiting similar recrystallisation rates to extruded formulations. HME is useful method of production of ASDs due to its continuous, high throughput nature and the increasing range of equipment available allows for a greater range of APIs and excipients to be processed successfully. However scCO2 impregnation is a promising production method for thermally labile compounds or high glass transition polymers that would traditionally require high levels of plasticiser. It is useful to consider a range of processing methods for formulation of poorly aqueous soluble drugs as not all methods will be suitable for all formulations.


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Table 1. Extrusion conditions for formulations. Drug loading [%] 10 30 50 10 30 50

Polymer PVP

SOL

Extrusion temperature [°C] 160 150 140 140 135 125

Table 2. Thermal characteristics of the pure materials prior to- and post-scCO2 treatment measured using a heating rate of 200 ⁰C/min. Standard deviations with n=3 are shown in brackets. aTgs estimated using the half-width method.

Pre-processing

Post processing

INM ∆H [J/g]

112.68 (3.32)

113.09 (1.02)

INM MP [⁰C]

175.38 (0.33)

178.52 (2.15)

PVP Tg [⁰C]a

128.56 (1.45)

131.10 (1.78)

SOL Tg [⁰C]a

83.49 (1.34)

82.28 (1.27)

Table 3. SFI processing conditions examined for the production of INM-SOL ASDs indicating the method development to produce completely amorphous solid dispersions containing Soluplus.

Identifier Drug loading [% w/w] SOLa 20 SOLb 20 SOLc 20 SOLd 20

Temperature [⁰⁰C] 60 60 70 70


Pressure [MPa] 10.0 15.0 10.0 15.0


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Table 4. Correlation factors were calculated using SpectrumIMAGE for the wavenumber range 1740-1545 cm-1, between each spectrum in the Raman map for each formulation and the spectrum for amorphous INM. Lowest and highest correlation factor as well as the range. The range of correlation factors is greater for SFI formulations than for the respective HME counterparts. Raman spectra correlation factors Formulation Highest and lowest

Range

10 PVP HME

0.980 – 0.966

0.014

10 PVP SFI

0.979 – 0.955

0.024

30 PVP HME

0.995 – 0.982

0.013

30 PVP SFI

0.985 – 0.968

0.017

10 SOL HME

0.981 – 0.969

0.012

10 SOL SFI

0.980 – 0.954

0.026

30 SOL HME

0.994 – 0.992

0.002

30 SOL SFI

0.988 – 0.975

0.013

Table 5. Physical and thermal properties used in the calculation of the glass transition temperature of amorphous solid dispersions predicted by the Gordon Taylor model. Density (g/cm3)

Tg (°C)

aINM

1.32

42.81

PVP

1.20

120.83

SOL

0.99

73.25


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Table 6. Glass transition of formulations measured by MDSC. Standard deviations with n=3 are shown in brackets. aGlass transition value predicted by Gordon-Taylor bNot completely amorphous. Drug [%] 10 30 50 10 30 50

Polymer PVP

SOL

HME 100.58 (2.86) 79.17 (2.44) 67.54 (0.30) 64.67 (0.47) 55.56 (1.92) 51.07 (1.46)

Tg [⁰C] SFI G-Ta 102.45 (0.77) 103.52 82.16 (2.00) 79.96 67.85 (1.67)b 64.69 63.63 (0.67) 65.22 58.57 (0.86) 56.52 57.57 (0.30)b 50.88

Table 7. Correlation factor R2 for a linear relationship between drug concentration and time for each formulation.

Formulation

R2

10 PVP SFI

0.711

30 PVP SFI

0.907

50 PVP SFI

0.804

10 PVP HME

0.953

30 PVP HME

0.962

50 PVP HME

0.988

10 SOL SFI

0.975

30 SOL SFI

0.976

50 SOL SFI

0.893

10 SOL HME

0.899

30 SOL HME

0.971

50 SOL HME

0.897



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Table 8. Enthalpy of melting measured using HyperDSC, heating rate 200 °C/min, following 4 months accelerated stability, storage conditions 40 ⁰C and 75 %RH. Standard deviations with n=3 are shown in brackets.

Formulation

∆H [J/g]

10 PVP SFI

6.87 (1.36)

10 PVP HME

2.61 (0.06)

30 PVP SFI

9.22 (2.61)

30 PVP HME

5.88 (1.38)

50 PVP HME

9.29 (2.98)

10 SOL SFI

0.00 (0.00)

10 SOL HME

0.09 (0.11)

30 SOL SFI

0.90 (0.65)

30 SOL HME

1.77 (0.81)

50 SOL HME

2.30 (0.60)


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Figure 1. Schematic representation of supercritical fluid impregnation apparatus including pressure vessel and ancillary equipment. 256x134mm (300 x 300 DPI)



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Figure 2. X-ray diffractograms of INM a) before and b) after treatment with scCO2. 144x111mm (96 x 96 DPI)


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Figure 3. FTIR spectra of (top) INM, (middle) PVP and (bottom) SOL, a) before and b) after treatment with scCO2. The increased intensity of the band at 2338 cm-1 indicates the presence of residual carbon dioxide which remained within the polymer following depressurisation. 150x213mm (96 x 96 DPI)



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Figure 4. Powder X-ray diffractograms of Soluplus/drug combinations processed using different conditions. Process conditions are detailed in Table 3. 142x111mm (96 x 96 DPI)


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Figure 5. PXRD diffractograms of a) 10 HME, b) 10 SFI, c) 30 HME, d) 30 SFI, e) 50 HME and f) 50 SFI indicating that an amorphous drug loading of 50% INM could be attained using HME for both PVP (top) and SOL (bottom) while only 30% was achieved using the SFI method. 120x162mm (96 x 96 DPI)



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Figure 6. Raman spectra collected from a 0.16 mm2 area of (left) PVP and (right) SOL formulations illustrating a) γ-INM, b) aINM, c) 10 HME, d) 10SFI, e) 30 HME, f) 30 HME, g) 50 HME, h) 50SFI, i) pure polymer. 287x202mm (96 x 96 DPI)


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Figure 7. Raman maps for collected for (top) 50 SOL HME and (bottom) 50 SOL SFI and the reference spectrum (aINM) using SpectrumIMAGE software. A sample of spectra collect from each spectrum is also shown. Higher correlation factors near 1 indicate a good similarity to aINM. 239x232mm (96 x 96 DPI)



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Figure 8. FTIR spectra illustrating the carbonyl stretching region of different drug loaded and processed (SFI versus HME) formulations 286x106mm (96 x 96 DPI)


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Figure 9. DSC thermograms of (left) INM-PVP and (right) INM-SOL formulations a) 10 HME b) 10 SFI c) 30 HME d) 30 SFI e) 50 HME f) 50 SFI. A single Tg is observed for all formulations, indicated by a tick 284x120mm (96 x 96 DPI)



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Figure 10. Dissolution profile of a) PVP HME b) PVP SFI c) SOL HME and d) SOL SFI formulations in pH 1.2. 50% (λ), 30% (ν),10% (π), crystalline INM (ϒ). 225x205mm (96 x 96 DPI)


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Figure 11. Graphical representation of AUC45min and AUC8hr for PVP (top) and SOL (bottom) formulations. * represents a statistical difference p

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