Influence of polymeric additive on the physical stability and

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Influence of polymeric additive on the physical stability and viscoelastic properties of aripiprazole Justyna Knapik-Kowalczuk, Krzysztof Chmiel, Karolina Jurkiewicz, Zaneta Wojnarowska, Mateusz Kurek, Renata Jachowicz, and Marian Paluch Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/ acs.molpharmaceut.9b00084 • Publication Date (Web): 08 Mar 2019 Downloaded from http://pubs.acs.org on March 10, 2019

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Molecular Pharmaceutics

Influence of polymeric additive on the physical stability and viscoelastic properties of aripiprazole Justyna Knapik-Kowalczuk1*, Krzysztof Chmiel1, Karolina Jurkiewicz1, Zaneta Wojnarowska1, MateuszKurek2, Renata Jachowicz2, Marian Paluch1 1Institute

of Physics, University of Silesia, SMCEBI, 75 Pułku Piechoty 1a, 41-500 Chorzów,

Poland 2Faculty

of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics,

Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland

*corresponding author: [email protected] TOC

KEYWORDS amorphous pharmaceuticals, Amorphous Solid Dispersions, physical stability, improvement stability, Hot Melt Extrusion, amorphous aripiprazole, rheological properties, rheology, dielectric spectroscopy, BDS

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ABSTRACT In this article, we investigated aripiprazole + Kollidon® VA64 (ARP/KVA) and aripprazole + Soluplus® (ARP/SOP) amorphous solid dispersions. Thermal properties of all prepared systems have been examined by means of Differential Scanning Calorimetry (DSC). Compositions revealing the recrystallization tendency were subsequently investigated by means of Broadband Dielectric Spectroscopy (BDS). On the basis of dielectric data, the physically stabile drug-polymer concentrations have been found. Finally, these systems have been investigated by rheology, which enables us to determine the minimal temperature required for dissolving the drug in the polymeric matrix, as well as the temperature dependence of the sample viscosity. Our investigations have shown that the amorphous form of the investigated anti-psychotic drug might be effectively stabilized by both employed polymers. However, due to the better stabilization effect and the more favorable rheological properties, KVA proved to be a better polymeric excipient for extrusion of amorphous aripiprazole.


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INTRODUCTION The amorphous Active Pharmaceutical Ingredients (APIs) and their molecular dispersions are produced on a large scale by two methods: Spray Drying (SD) and Hot Melt Extrusion (HME)1,2,3,4,5. The latter, classified as a solvent-free process, includes three stages: (i) heating and softening of a physical mixture containing API and thermoplastic polymer inside the extruder; (ii) pressurization of the molten mass through a die; (iii) formation of granules, cylinders or films6,7. In this process, the most critical parameter is temperature8. Overheating may result in thermal decomposition of the sample9,10 or an excessive softening of material causing difficulties in formation of a final dosage form. On the other hand, when the manufacturing temperature is too low the dissolution of an API in the polymeric matrix might become impossible. Additionally, the material might not be viscous enough for extrusion process4. Choosing an appropriate processing condition requires keeping in mind the possibility of sample re-crystallization11,12,13. Therefore, a priori selection of a drugpolymer composition that is physically stable at the elevated temperatures associated with extrusion is required to guarantee the success of this operation14. In the current work, we focused on disordered aripiprazole (ARP) drug. It has been found that neat amorphous ARP reveals a high re-crystallization tendency in the supercooled liquid state (i.e. above Tg)15. It is worth noting that aripiprazole is one of the best-selling crystalline pharmaceuticals. ARP belongs to a new generation of antipsychotic drugs16. It is used in the treatment of schizophrenia, acute manic as well as mixed episodes associated with bipolar disorders17,18. From the chemical point of view, ARP can be classified as a benzisoxazole derivative containing a dihydrocarbostyril ring and a dichlorophenylpiperazinyl unit located on two opposite ends of the molecule and the butoxyl chain in between. The molecular structure of ARP compound is presented in Figure 1a.



Figure 1. Chemical structure: (a) ARP, (b) SOP, and (c) KVA.

Due to its unique flexible structure, ARP has the ability to form multiple conformational polymorphs19. Golberg and Griesser established nine different crystalline forms of this substance20,21 that make it the most polymorphic drug in the Cambridge Structural Database (CSD)22. It is well known that different polymorphic structures very often possess different physical and chemical properties, such as melting point, density, reactivity, solubility, bioavailability, etc.23. Therefore, choosing an appropriate crystalline form gives an opportunity to get the desired properties of a pharmaceutical compound24. Nevertheless, with too many polymorphic forms some uncontrolled transformations between them might occur25. This can lead to changes in drug efficiency, resulting in serious health problems for patients, and can also entail huge financial losses for pharmaceutical companies. In this, work we present insights into the processing technology of amorphous solid dispersions by HME. For this purpose, several binary compositions of ARP and two copolymers – Kollidon® VA64 (KVA) and Soluplus® (SOP) have been prepared. The initial characterization of these mixtures have been performed by means of Differential Scanning Calorimetry (DSC). Dielectric measurements have been employed to find the most physically stable binary compositions. Next, these particular systems were investigated by means of rheology, to determine both the minimal temperature required for dissolving the drug in the polymeric matrix, as well as the temperature dependence of the viscosity. These experiments enable us to address two questions: (i) Which polymer, KVA or SOP, works better as a


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stabilizer of the amorphous ARP? (ii) Which ARP-polymer composition seems to be better for HME technology? EXPERIMENTAL METHODS Materials Aripiprazole (ARP) (Mw = 448.38 g/mol) drug was purchased from ZCL Chemicals Limited (Dist. Bharuch, Gujarat, India). This pharmaceutical is described chemically as 7-{4[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-1,2,3,4-tetrahydroquinolin-2-one.

Kollidon®

VA64 (KV64) (MW = 45 000 − 47 000 g/mol) with degradation temperature equal to 543 K26 and Soluplus® (SOP) (MW = 90 000 – 140 000 g/mol) with degradation temperature equal to 551 K26 were purchased from BASF (Germany). The chemical names of these copolymers are as follows: vinylpyrrolidone – vinyl acetate copolymer and polyvinyl caprolactam – polyvinyl acetate – polyethylene glycol graft copolymer, respectively. Physical mixtures of ARP/KVA and ARP/SOP contacting 20, 50, 70 and 90 wt.% of the polymer were prepared by mixing two components in appropriate weight ratios. Differential Scanning Calorimetry (DSC) Thermal properties of KVA, SOP, ARP, and the ARP-based mixtures containing various ratios of the KVA or SOP polymer were examined by means of a Mettler Toledo DSC 1 STARe System. The samples were measured in aluminum crucibles with a 40 µL volume. All DSC experiments were carried out over the same temperature range, from 293 K to 428 K with a heating rate equal to 10 K/min. The amorphous forms of neat ARP and its mixtures were cooled in-situ with a cooling rate equal to 30 K/min. The measuring device was equipped with an HSS8 ceramic sensor including 120 thermocouples, and a liquid nitrogen cooling accessory. The instrument was calibrated for temperature and enthalpy employing zinc and indium standards. Melting points were determined as the onset of the peak, while the glass transition temperatures were obtained from the midpoint of the heat capacity increment.

Broadband Dielectric Spectroscopy (BDS) Molecular dynamics of ARP/KVA 20wt.% and ARP/SOP 20wt.% was investigated by means of a Novo-Control GMBH Alpha dielectric spectrometer. Dielectric spectra were registered in the broad frequency range 10-1 Hz - 106 Hz during heating from T ~ Tg up to 395 K with a step of 1 K. During dielectric experiments the temperature was controlled by a 5 ACS Paragon Plus Environment


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Quatro temperature controller with temperature stability better than 0.1 K. Prior to the BDS experiments the samples were quench cooled on the heating plate at T = 420 K and air atmosphere for t < 1 min. The samples were measured in a parallel-plate cell made of stainless steel (diameter of 15 mm, and a 0.1 mm gap provided by silica spacer fibers). In order to determine the values of τα and τα’ of ARP/KVA 20wt.% and ARP/ SOP 20wt.% at various temperatures, the dielectric loss spectra were fitted by the Havrilak - Negami (HN) function:

 * HN ( )   ' ( )  i " ( )    



1  i

a 

b

HN

(1)

where ε′ and ε″ are real and imaginary parts of the complex dielectric permittivity, ε∞ denotes the high frequency limit permittivity, ∆ε the dielectric strength, ω is equal to 2πf, τHN is the HN relaxation time, while a and b are symmetric and asymmetric broadening parameters. The obtained fitting parameters were then used to calculate the values of τα and (τα)’ by means of the equation: 1

  / '

1   a  a   ab   sin   sin    HN   2  2b    2  2b 



1 a

(2)

The temperature evolution of the structural (α- or α’-) relaxation time was parameterized by the Vogel-Fulcher-Tamman (VFT) equation:  DT0    T  T0 

  /  ' T     exp

(3)

where τ∞, T0, and D are fitting parameters. Rheological studies The viscoelastic properties of both physical mixtures and amorphous solid dispersions containing ARP/KVA 70wt.% and ARP/SOP 85wt.% were measured by means of an ARES G2 Rheometer, using an aluminum parallel plate geometry (diameter = 8 mm); the gap was 1 mm. The temperature ramp measurements were conducted at a constant frequency of 10 rad/s and strain (Tg, it is impossible to reach the ‘shadowed area’ of viscosity, and consequently to produce this pharmaceutical via HME (see Figure 7a). The situation is completely different for amorphous ARP/KVA and ARP/SOP compositions. The minimum temperature at which ARP/KVA 70wt.% has a viscosity suitable for HME is 398 K. It is worth noting that at this particular temperature, the API dissolves into the polymer from the physical mixture. A different situation is found for ARP/SOP 85wt.% composition. The viscosity suitable for HME is achieved at 413 K, while the temperature required for dissolution of ARP in the polymer matrix is significantly lower (T = 383 K; see Figure 7c and the viscosity spectrum marked in brown therein). Thus, although the ARP/SOP 85wt.% can form an ideal SD at 383 K, its viscosity at this temperature is too high to be produced using the HME process. Taking into account three parameters: (i) the minimum amount of a polymer required for stabilization of an amorphous API, (ii) the minimum temperature needed to dissolve the drug into the polymer matrix from a physical mixture, and (iii) the minimum temperature at 15 ACS Paragon Plus Environment


which ASD has a viscosity in the range of 800 - 10 000 Pa·s, one concludes that KVA is a better polymeric excipient for HME of amorphous ARP than SOP. This conclusion is supported by Figure S1 in Supporting Information. According to the decision process for properly selecting the type and amount of polymer for HME, three questions need to be asked: First, whether the drug-polymer system is oversaturated? If not, no further stabilization studies are required, and the second question arises: Is HME a preferred production method of this ASD? If the answer is positive, it should be determined if this polymer ensures the lowest operating temperature. If the answer to this question is also positive, the system is a viable candidate for production/rescaling. Long-term physical stability studies of ARP-based ASDs To verify that the samples of ARP/KVA 70wt.% and ARP/SOP 85wt.% prepared in the previous step are indeed fully amorphous, we carried out XRD measurements. The X-ray diffraction patterns of both compositions containing ARP/KVA and ARP/SOP, as well as neat crystalline and amorphous ARP are presented in Figure 8. As can be seen, none of the X-ray patterns of the freshly prepared drug-polymer systems exhibit sharp Bragg peaks indicative of crystallinity. Since the appropriately stable drug-polymer concentrations have been prepared at temperature ca. 60 K higher than the room temperature, at the lower temperature, e.g. RT, the solubility limit is shifted to lower API concentration, disturbing the thermodynamic stability41,42,43. Therefore, at RT the systems are in fact supersaturated by API. Accordingly, additional

X-ray diffraction measurements to assess long-term physical stability were

performed. As seen in Figure 8, the XRD patterns collected after 220 days storage of ARP compositions at 298 K are characterized by broad amorphous halos, similarly to the samples measured immediately after preparation; this confirms the absence of re-crystallization . These results indicate that systems containing ARP/KVA 70wt.% and ARP/SOP 85 wt.% are have high physical stability even if stored at RT i.e., at temperatures for which the API and polymer systems form supersaturated solutions.


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Figure 8. The X-ray diffraction patterns for neat crystalline ARP (black line), neat amorphous ARP (purple line), freshly prepared ARP/KVA 70wt.% system, ARP/KVA 70wt.% system stored 110 and 220 days at ambient conditions T = 298 K and RH = 25% (orange lines), freshly prepared ARP/SOP 85wt.% system, ARP/SOP 85wt.% system stored 110 and 220 days at ambient conditions T = 298 K and RH = 25% (blue lines).



CONCLUSIONS In this paper the ARP/KVA and ARP/SOP systems were examined in terms of three criteria: (i) the physical stability of these compositions at both manufacturing and standard storage conditions, (ii) the minimum temperature needed to dissolve the crystalline API into the polymeric matrix, and (iii) the minimum temperature at which the drug-polymer composition have a viscosity appropriate for HME. The DSC experiments herein indicate that KVA is a better stabilizer of amorphous ARP than SOP. From dielectric measurements the lowest concentrations that guarantee thermodynamic stability at the manufacturing temperature of the drug-polymer systems have been determined. The minimum amount of KVA and SOP polymer to fully stabilize ARP is equal to 70 and 85 wt. %, respectively. Taking into account that a drug-polymer solubility limit shifts toward lower API concentration with decreasing temperature, at standard storage conditions, i.e. room temperature, the ARP-based compositions containing 70 wt. % of KVA or 85 wt. % of SOP are in the supersaturated, and consequently thermodynamically unstable region. To investigate the long-term physical stability of ARP/KVA 70wt.% and ARP/SOP 85wt.% systems stored at room temperature, XRD studies were performed. The results indicate that the systems are physically stable for a minimum of 220 days when stored at T = 398 K and RH = 25%. Finally, based on rheological data both the lowest temperature needed to dissolve the API into the polymer matrix, as well as the lowest temperature suitable for extrusion have been determined. These experiments demonstrated that a physically stable ARP-based composition containing SOP, despite having a lower Tg than ARP/KVA, required a higher operating temperature. The minimal manufacturing temperature of ARP/KVA 70wt.% is 398 K, while ARP/SOP 85wt.% of SOP should be processed at least at T = 413 K. This result indicates that KVA is a better additive for ARP’s HME than SOP, first, because a lower processing temperature can be employed, and second, because the drug is stabilized more effectively with the use of KVA (specifically, less polymer is needed to obtain the same degree of stabilization). Finally, our investigation showed that the assumption the temperature suitable for HME is equal to Tg + 40 K is not valid in all cases. A counterexample is the mixture containing ARP/SOP 85wt.%, for which based on viscosity data, the optimal HME temperatureis Tg + 76 K.

ACKNOWLEDGEMENT 18 ACS Paragon Plus Environment

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The authors, K.C., M.K., R.J. and M.P., are grateful for the financial support received within the Project No. 2015/16/W/NZ7/00404 (SYMFONIA 3) from the National Science Centre, Poland. The authors are thankful to Dr. C. M. Roland from Naval Research Laboratory Washington for providing useful comments on the manuscript. Supporting Information The decision tree of the polymer choice for Hot Melt Extrusion. According to the decision tree to properly select the type and amount of polymer for HME, three questions need to be asked. First, whether the drug-polymer system is oversaturated? If not, no further stabilization studies are required, and consequently, the second question might be asked. Do the HME is a preferred production method of this ASD? If the answer is positive it should be investigated if this polymer ensures the lowest operating temperature. If the answer for the latter question is also positive the system is ready for production/rescaling.



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