Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG

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Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG 517 in HPMC-AS using DSC, Solid State NMR and Solution Calorimetry Julie L Calahan, Stephanie C Azali, Eric J. Munson, and Karthik Nagapudi Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.5b00556 • Publication Date (Web): 12 Oct 2015 Downloaded from http://pubs.acs.org on October 20, 2015

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Molecular Pharmaceutics

Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG 517 in HPMC-AS using DSC, Solid State NMR and Solution Calorimetry Julie L. Calahan1,2, Stephanie C. Azali1, Eric J. Munson2, Karthik Nagapudi3,*

Abstract Intimate phase mixing between the drug and the polymer is considered a prerequisite to achieve good physical stability for amorphous solid dispersions. In this paper, spray dried amorphous dispersions (ASDs) of AMG 517 and HPMC-as were studied by DSC, Solid state NMR (SSNMR) and solution calorimetry. DSC analysis showed a weakly asymmetric (∆Tg ~ 13.5) system with a single glass transition for blends of different compositions indicating phase mixing. The Tg-composition data was modeled using the BKCV equation to accommodate the observed negative deviation from ideality. Proton Spin lattice relaxation times in the laboratory and rotating frames (1H T1 and T1ρ), as measured by SSNMR, were consistent with the observation that the components of the dispersion were in intimate contact over a 10-20 nm length scale. Based on the heat of mixing calculated from solution calorimetry and the entropy of mixing calculated from the Flory-Huggins theory, the free energy of mixing was calculated. The free energy of mixing was found to be positive for all ASDs, indicating that the drug and polymer are thermodynamically predisposed to phase separation at 25°C. This suggests that miscibility measured by DSC and SSNMR is achieved kinetically as the result of intimate mixing between drug and polymer during the spray drying process. This kinetic phase mixing is responsible for the physical stability of the ASD.

Keywords: Amorphous solid dispersion, solution calorimetry, Flory-Huggins, physical stability, phase mixing

1. 2. 3.

Oral Delivery Product and Process Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, USA. Current address: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, USA. Current Address: Small Molecule Pharmaceutical Sciences, Genentech Inc, 465 East Grand Avenue, South San Francisco, CA, USA.

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Introduction Amorphous solid dispersion (ASD) has now been established as a robust formulation platform to address bioavailability associated with solubility/dissolution-limited compounds.1-4 As amorphous systems are thermodynamically unstable, recrystallization of the drug from the dispersion is a liability in the development of ASDs. From the standpoint of physical stability, complete miscibility of the API and the polymer is desired where the amorphous drug is molecularly dispersed in the polymer carrier. Phase separation between the components of the ASD is usually the first step toward recrystallization of API and it is therefore important to understand the thermodynamics of phase mixing between the API and polymer.5-8 Flory-Huggins (F-H) lattice theory has been the cornerstone for understanding thermodynamics of polymer-solvent and polymer-polymer systems.9, 10 The situation of interest here, where the small molecule API is dispersed in a polymer, can be approximated to the situation of a polymer-solvent system thereby facilitating the use of F-H lattice theory to describe these systems. The free energy change accompanying mixing of an API and polymer at a particular temperature and pressure is given by: ∆Gm = ∆H m − T∆S m

(1)

where ∆Hm is the enthalpy change and ∆Sm is the entropy change accompanying mixing. ∂ 2 Gm For complete miscibility the conditions of ∆Gm ≤ 0 and > 0 must be ∂x 2 ∂ 2 Gm simultaneously satisfied, where > 0 is the stability term. According to the F-H ∂x 2 theory, the entropy change is given by:

φ   ∆S m = − R φdrug ln φdrug + polymer ln φ polymer  m  

(2)

where R is the universal gas constant, Φ is the volume fraction and m is the ratio of the volume of the polymer chain to a lattice site (which is considered the same as the volume of the drug molecule). There are several assumptions made in the F-H theory that pose limitations to wide applicability of the model. However, for the purpose of understanding basic thermodynamics of mixing, the theory is adequate. Given that the ∆Sm is always favorable, miscibility will depend on the sign and magnitude of ∆Hm. The enthalpy of mixing in the F-H model is usually described in terms of an interaction parameter (χ). ∆H m = RTχφdrugφ polymer

(3)

When using the F-H theory for pharmaceutical systems, the primary focus has been on methods to evaluate χ. There have been a number of reports in pharmaceutical literature



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where different methods to estimate χ and their merits have been discussed. Primarily the methods to estimate χ fall into two categories, (a) melting point depression approach and (b) solubility parameter based approach.5, 8, 11, 12 The χ value calculated from the melting point depression approach is only valid at temperatures near the melting point of the API. Therefore, the value obtained using this approach cannot be extrapolated to lower temperatures, which are typically the temperatures of interest for storage of pharmaceuticals. Moreover, the method also may suffer from experimental difficulties associated with adequate mixing of the crystalline API and the polymer. The solubility parameter based approach was originally intended to describe non-polar systems. This approach has been adapted to describe systems with interactions such as hydrogen bonding. Solubility parameter of the API and the polymer can be calculated using a group contribution approach such as Van-Krevlen method. Alternatively the solubility parameter can also be predicted using molecular modeling tools13 that calculate the cohesive energy density at a particular temperature. The solubility parameter approach is attractive as it can provide the necessary values to calculate χ without recourse to experimentation. However, as there are different ways to estimate the solubility parameter, the results from these methods can also vary resulting in different values of χ at a particular temperature. In order to circumvent issues with solubility parameter approach, Taylor and coworkers5 have used solubility determination of the API in small molecular weight analogs of the polymer to determine χ. This method also suffers from issues of extrapolating the results from analogs to the system of interest. In order to incorporate temperature dependence of χ, Zhao et al. and Tian et. al.8, 11 have combined the melting point depression and the solubility parameter approach. This methodology facilitates obtaining χ as a function of temperature, thereby allowing for the construction of the temperature-composition phase diagram of the API-polymer system. All the methods described so far while very useful, have some issues in terms of accuracy and experimental difficulties. From this perspective, it would be interesting to apply a method that can experimentally measure heat of mixing in lieu of trying to compute it from measured or predicted values of χ. In this paper, we describe a heat of solutionbased methodology to measure heat of mixing. The application of this method to polymer-polymer blends has been described previously.14-17 This method is based on the application of Hess’ law to calculate the heat of mixing from the heat of solution of API, polymer and the API-polymer blends in a suitable solvent. The method is employed to compute heat of mixing and subsequently the free energy of mixing for a variety of polymer-API compositions made by spray drying at room temperature. In such high viscosity blends, the system is usually far from equilibrium and the phase mixing and demixing is controlled by kinetics to a large extent and as such the as-is state of the system also needs to be understood. In this paper, glass transition temperature measurements using differential scanning calorimetry and relaxation time measurements using solid state NMR spectroscopy have been used to gain an understanding of the phase mixing in the blends immediately after manufacture. AMG 517 was developed as a potent and selective antagonist of VR1 indicated in the treatment of acute and chronic pain. The structure of AMG 517 is shown in Figure 1. AMG 517 is a BCS Class II drug molecule that has a low bioavailability due to


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solubility-limited absorption. The physico-chemical properties of AMG 517 are summarized in Table 1. Based on superior in-vivo performance following oral administration in male Sprague-Dawley rats the Sorbic acid cocrystal of AMG 517 was selected for clinical development over AMG 517 freebase.18 In previous publications it has also been shown that AMG 517 when formulated as an amorphous solid dispersion gave exposures better than what was observed with the cocrystal when tested in cynomologus monkeys. Kennedy et. al.19 and Calahan et. al.20 have described the method of preparation and properties of an ASD of AMG 517 with HPMC-as. Due to the availability of material and long-term physical and chemical stability data, this system was selected for use in the current study. Table 1. Physicochemical properties of AMG 51719 Molecular formula Molecular weight (g/mol) Log P pKa Intrinsic solubility (µg/mL)

C20H13F3N4O2S 430.4 5.1 1.8 ~ 0.05 O

F

F

NH CH3

N

F O N

S

N

Figure 1. Molecular structure of AMG 517.

Materials and Methods Materials: AMG 517 drug substance was manufactured at Amgen, Inc., as a highly crystalline powder and was used as-received for the studies described in this paper. Hydroxypropyl methylcellulose acetate succinate (HPMC-as), was purchased from ShinEtsu. ASDs of AMG 517 with HPMC-as-MF were spray dried at drug loads of 15%, 30%, 50%, 62%, 75%, 82% and 95% active by weight. In addition, pure polymer and pure drug were also spray dried. Physical mixtures of the pure spray dried materials were prepared at 50% and 75% drug load using a Labram acoustic mixer. Spray drying: The ASDs were spray dried using a modified B-290 Buchi Mini system with an ultrasonic nozzle configuration. Solutions for spray drying were prepared by dissolving AMG 517 and HPMC-AS in ethyl acetate at 25 mg/ml total concentration. Spray dry conditions were as follows: Inlet Temperature: 75°C, Outlet Temperature: ~50°C, Drying gas flow: 0.34 kg/min, Atomizing gas pressure: ~70 psi and Feed flow



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rate: 2.0 ml/min. The ASDs were then dried to < 0.2% residual solvent prior to characterization. Solution Calorimetry: A Precision Solution Microcalorimeter was used with a TAM 2277 (TA Instruments, DE, USA) temperature controlled water bath at 25°C (298K). DMSO was used as the solvent for solution calorimetry experiments. Approximately 100 mg of sample was loaded into ampoules and sealed with wax using a butane burner. Stirrer speed was 600 rpm and the break time was 15 minutes. Linear drift settings in the software were used to calculate heat of solution for all the samples. KCl in water and TRIS in 0.1N HCl were used as standard checks to verify the instrument calibration. X-Ray Powder Diffraction (XRPD): A Phillips X’Pert diffractometer was used to collect x-ray diffraction patterns. A CuKα source with a fixed slit was used, with 45kV and 40mA power. Experiments were conducted at room temperature, between 3° to 40° 2theta, in 0.00837° steps, 35.56 sec/°, 3823 steps. The stage was rotated with a revolution time of 2.000 seconds. Modulated Differential Scanning Calorimetry (mDSC): A DSC Q1000 (TA Instruments, DE, USA) system was used with crimped aluminum DSC pans and dry nitrogen purge. A heating ramp of 5°C/min was applied from 25 to 250°C with modulation amplitude of +/- 0.5°C applied every 30 seconds. SSNMR: All SSNMR measurements were conducted using a Bruker DSX spectrometer (Bruker Biospin, MA, USA) operating at a 1H resonance frequency of 600 MHz. A Bruker 4mm double resonance magic angle spinning HX MAS probe was used to record all NMR data and samples were spinning at 14kHz. 1H T1 and T1ρ were measured through 13C using cross polarization. A saturation recovery sequence was inserted prior to the CP sequence for 1H T1 measurement. 1H T1ρ was measured by using a spin-lock sequence after the 1H 90º pulse. A radio-frequency field of 60 kHz was used for the spinlock field. A recycle delay of 10s was used and 256 scans per time point were collected for signal-to-noise averaging. A CP contact time of 2 ms was used and a spinal-64 sequence with pulse length of 5−µs was used for 1H decoupling. 1H T1 and T1ρ of the API and polymer were measured by integrating appropriate ppm regions which are devoid of spectral interference. All data fitting was done using Sigmaplot software (Systat, San Jose, CA). The 1H T1 value was calculated by fitting intensity-recovery time data by: −t T1

M (t ) = M 0 (1 − e )

and 1H T1ρ was calculated by fitting intensity-decay time data by:

M (t ) = M 0 e

−t T 1ρ

where M is the integrated signal intensity at a time t and M0 is an amplitude parameter from the fit.


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Results and Discussion Figure 2(a) shows the XRPD patterns of the crystalline and amorphous phases of AMG 517. The XRPD pattern of the as-received crystalline material conforms to a phase referred to as Form I with prominent peaks at 15.9, 18.6, and 19.0 ° 2θ. In contrast to the well-resolved XRPD pattern of the crystalline material, the spray dried material shows a broad halo characteristic of amorphous materials. Figure 2(b) shows the DSC thermograms of the crystalline and amorphous freebase of AMG 517. The crystalline freebase has a melting point onset of 229 °C (event A) with an associated heat of fusion of 37.7 kJ/mol. The spray dried amorphous freebase made by spray drying has mid-point glass transition (Tg) of 110 °C (event B) as measured by MDSC at a heating rate of 5 °C/min. Subsequent to glass transition the material displays an exotherm (event C) associated with crystallization of the sample. Amorphous solid dispersions of AMG 517 with HPMC-as were made in the following compositions using spray drying: 15%, 30%, 50%, 75%, 82% and 95% active by weight. The dispersions were subjected to secondary drying to reduce the solvent content to 15%) is expected to be phase separated. In these systems, it is more meaningful to extract kinetic state of the as-prepared samples to gauge physical stability.

Conclusions Spray dried amorphous dispersions of AMG 517 and HPMC-as were studied by DSC, SSNMR and solution calorimetry. A single glass transition was observed for all blends and the Tg-composition data shows a weakly asymmetric system with a negative deviation from ideality. 1H T1 and T1ρ values measured by SSNMR for the API and the polymer were found to be equivalent and the domain size calculations suggested that the components of the blend were intimately mixed on a 10-20 nm length scale. The use of appropriate spin diffusion coefficient values to estimate domain sizes was highlighted. The use of solution calorimetry for measuring heat of mixing and thereby free energy of mixing was demonstrated. Free energy of mixing was found to be positive for all ASDs, indicating that the drug and polymer are thermodynamically predisposed to phase separation at 25°C. However, the ASDs were found to be phase mixed after the spray



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drying process. This suggests that phase mixing is achieved as the result of intimate mixing between drug and polymer during the spray drying process. This kinetic phase mixing is responsible for the physical stability of the ASD. Presumably, kinetic phase mixing is the major stabilizing force in general for ASDs.


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Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG

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