Purpose
To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation ...and stability of these amorphous systems.
Methods
Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (
T
g
).
13
C and
15
N solid-state NMR was utilized to investigate changes in local structure and protonation state, while
1
H
T
1
and
T
1ρ
relaxation measurements were used to probe miscibility and phase behavior of the dispersions.
Results
T
g
values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction.
15
N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at −360.7 ppm (unprotonated) and −344.4 ppm (protonated). Additionally,
1
H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.
Conclusions
15
N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Bruton’s tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies ...have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.
This study investigated the presence of specific drug–excipient interactions in amorphous solid dispersions of lapatinib (LB) and four commonly used pharmaceutical polymers, including Soluplus, ...polyvinylpyrrolidone vinyl acetate (PVPVA), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose phthalate (HPMCP). Based on predicted pK a differences, LB was hypothesized to exhibit a specific ionic interaction with HPMCP, and possibly with HPMCAS, while Soluplus and PVPVA were studied as controls without ionizable functionality. Thermal studies showed a single glass transition (T g) for each dispersion, in close agreement with predicted values for Soluplus, PVPVA, and HPMCAS systems. However, the T g values of LB–HPMCP solid dispersions were markedly higher than predicted values, indicating a strong intermolecular interaction between LB and HPMCP. 15N solid-state NMR provided direct spectroscopic evidence for protonation of LB (i.e., salt formation) within the HPMCP solid dispersions. 1H T 1 and 1H T 1ρ relaxation studies of the dispersions supported the ionic interaction hypothesis, and indicated multiple phases in the cases of excess drug or polymer. In addition, the dissolution and stability behavior of each system was examined. Both acidic polymers, HPMCAS and HPMCP, effectively inhibited the crystallization of LB on accelerated stability, likely owing to beneficial strong intermolecular hydrogen and/or specific ionic bonds with the acidic polymers. Soluplus and PVPVA showed poor physical properties on stability and subsequently poor crystallization inhibition.
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Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility, and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals ...are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is a powerful probe of structure in cocrystals and salts of APIs; however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here, relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiment times by 1–2 orders of magnitude for salts and cocrystals of a complex API. The large sensitivity gains from DNP facilitates rapid acquisition of natural isotopic abundance 13C and 15N solid-state NMR spectra. Critically, DNP enables double resonance 1H–15N solid-state NMR experiments such as 2D 1H–15N HETCOR, 1H–15N CP-build up, 15N{1H} J-resolved/attached proton tests, 1H–15N DIPSHIFT, and 1H–15N PRESTO. The latter two experiments allow 1H–15N dipolar coupling constants and H–N bond lengths to be accurately measured, providing an unambiguous assignment of nitrogen protonation state and definitive classification of the multicomponent solids as cocrystals or salts. These types of measurements should also be extremely useful in the context of polymorph discrimination, NMR crystallography structure determination, and for probing hydrogen bonding in a variety of organic materials.
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Fast magic‐angle spinning (MAS), frequency selective (FS) heteronuclear multiple quantum coherence (HMQC) experiments which function in an analogous manner to solution SOFAST HMQC NMR experiments, ...are demonstrated. Fast MAS enables efficient FS excitation of 1H solid‐state NMR signals. Selective excitation and observation preserves 1H magnetization, leading to a significant shortening of the optimal inter‐scan delay. Dipolar and scalar 1H{14N} FS HMQC solid‐state NMR experiments routinely provide 4‐ to 9‐fold reductions in experiment times as compared to conventional 1H{14N} HMQC solid‐state NMR experiments. 1H{14N} FS resonance‐echo saturation‐pulse double‐resonance (RESPDOR) allowed dipolar dephasing curves to be obtained in minutes, enabling the rapid determination of NH dipolar coupling constants and internuclear distances. 1H{14N} FS RESPDOR was used to assign multicomponent active pharmaceutical ingredients (APIs) as salts or cocrystals. FS HMQC also provided enhanced sensitivity for 1H{17O} and 1H{35Cl} HMQC experiments on 17O‐labeled Fmoc‐alanine and histidine hydrochloride monohydrate, respectively. FS HMQC and FS RESPDOR experiments will provide access to valuable structural constraints from materials that are challenging to study due to unfavorable relaxation times or dilution of the nuclei of interest.
Frequency selective (FS) 1H{14N} HMQC and RESPDOR solid‐state NMR experiments provide four‐ to ninefold reductions in experiment times, permitting the fast acquisition of 2D 1H{14N} HMQC spectra and rapid measurements of NH bond lengths in organic materials (see figure).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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The purpose of this study was to determine the drug-polymer miscibility of GENE-A, a Genentech molecule, and hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), a polymer, ...using computational and experimental approaches. The Flory-Huggins interaction parameter,χ, was obtained by calculating the solubility parameters for GENE-A and HPMC-AS over the temperature range of 25–100°C to obtain the free energy of mixing at different drug loadings (0–100%) using the Materials Studio modeling and simulation platform (thermodynamic approach). Solid-state nuclear magnetic spectroscopy (ssNMR) was used to measure the proton relaxation times for both drug and polymer at different drug loadings (up to 60%) at RT (kinetic approach). Thermodynamically, the drug and polymer were predicted to show favorable mixing as indicated by a negative Gibbs free energy of mixing from 25 to 100°C. ssNMR showed near identical relaxation times for both drug and polymer in the solid dispersion at RT and 40°C for a period up to 6 months showing phase mixing between the API and polymer on <10nm scale. Orthogonal computational and experimental approaches indicate phase mixing of the system components.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Active pharmaceutical ingredients (APIs) can be prepared in many different solid forms and phases that affect their physicochemical properties and suitability for oral dosage forms. The development ...and commercialization of dosage forms require analytical techniques that can determine and quantify the API phase in the final drug product. 13C solid-state NMR (SSNMR) spectroscopy is widely employed to characterize pure and formulated solid APIs; however, 13C SSNMR experiments on dosage forms with low API loading are often challenging due to low sensitivity and interference from excipients. Here, fast magic angle spinning 1H SSNMR experiments are shown to be applicable for the rapid characterization of low drug load formulations. Diagnostic 1H SSNMR spectra of APIs within tablets are obtained by using combinations of frequency-selective saturation and excitation pulses, two-dimensional experiments, and 1H spin diffusion periods. Selective saturation pulses efficiently suppress the broad 1H SSNMR signals from the most commonly encountered excipients such as lactose and cellulose, allowing observation of high-frequency API 1H NMR signals. 1H SSNMR provides a 1–3 orders of magnitude reduction in experiment time compared to standard 13C SSNMR experiments, enabling diagnostic SSNMR spectra of dilute APIs within tablets to be obtained within minutes. The 1H SSNMR spectra can be used for quantification, provided calibrations are performed on a standard sample with known API loading.
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Solubility enhancement has become a common requirement for formulation development to deliver poorly water soluble drugs. Amorphous solid dispersions (ASDs) and salt formation have been two ...successful strategies, yet there are opportunities for further development. For ASDs, drug–polymer phase separation may occur at high drug loadings during dissolution, limiting the increase of drug loadings in ASD formulations. For salt formation, a salt form with high crystallinity and sufficient solid-state stability is required for solid dosage form development. This work studied the effect of counterions on the dissolution performance of ASDs. Surface area normalized dissolution or intrinsic dissolution methodology was employed to eliminate the effect of particle size and provide a quantitative comparison of the counterion effect on the intrinsic dissolution rate. Using indomethacin (IMC)–poly(vinylpyrrolidone-co-vinyl acetate) ASD as a model system, the effect of different bases incorporated into the ASD during preparation, the molar ratios between the base and IMC, and the drug loadings in the ASD were systematically studied. Strong bases capable of ionizing IMC significantly enhanced drug dissolution, while a weak base did not. A physical mixture of a strong base and the ASD also enhanced the dissolution rate, but the effect was less pronounced. At different base to IMC molar ratios, dissolution enhancement increased with the base to IMC ratio. At different drug loadings, without a base, the IMC dissolution rate decreased with the increase of drug loading. After incorporating a strong base, it increased with the increase of drug loading. The observations from this study were thought to be related to both the ionization of IMC in ASDs and the increase of microenvironment pH by the incorporated bases. With the significant enhancement of the drug dissolution rate, our work provides a promising approach of overcoming the dissolution limitation of ASD formulations at high drug loadings.
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Usage of the amorphous phase of compounds has become the method of choice to overcome oral bioavailability problems related to poor solubility. Due to the unstable nature of glasses, it is clear that ...the method of preparation of the amorphous glass will have an impact on physical/chemical stability and in turn in vivo performance. The method of preparation can also have a profound impact on the mechanical properties of the amorphous phase. We have explored the impact of preparation method on the mechanical properties of an amorphous solid dispersion using a development compound, GDC-0810. Three methods were used to generate amorphous solid dispersions (ASDs) of 50% GDC-0810 with hydroxypropyl methylcellulose acetate succinate: (1) spray drying, (2) coprecipitation using overhead mixing, and (3) coprecipitation using resonant acoustic mixing. All 3 methods were found to generate ASDs with good phase mixing and similar glass transition temperatures. Coprecipitated ASD powders (overhead mixing and resonant acoustic mixing) demonstrated superior tabletability and flow properties when compared to the spray drying powder. Careful choice of manufacturing process can be used to tune material properties of ASDs to make them more amenable for downstream operations like tableting. Acoustic mixing has been demonstrated as a scalable new method to make ASDs through coprecipitation.
A variety of particle sizes of a model compound, dicumarol, were prepared and characterized in order to investigate the correlation between particle size and solid-state NMR (SSNMR) proton ...spin–lattice relaxation (1H T 1) times. Conventional laser diffraction and scanning electron microscopy were used as particle size measurement techniques and showed crystalline dicumarol samples with sizes ranging from tens of micrometers to a few micrometers. Dicumarol samples were prepared using both bottom-up and top-down particle size control approaches, via antisolvent microprecipitation and cryogrinding. It was observed that smaller particles of dicumarol generally had shorter 1H T 1 times than larger ones. Additionally, cryomilled particles had the shortest 1H T 1 times encountered (8 s). SSNMR 1H T 1 times of all the samples were measured and showed as-received dicumarol to have a T 1 of 1500 s, whereas the 1H T 1 times of the precipitated samples ranged from 20 to 80 s, with no apparent change in the physical form of dicumarol. Physical mixtures of different sized particles were also analyzed to determine the effect of sample inhomogeneity on 1H T 1 values. Mixtures of cryoground and as-received dicumarol were clearly inhomogeneous as they did not fit well to a one-component relaxation model, but could be fit much better to a two-component model with both fast-and slow-relaxing regimes. Results indicate that samples of crystalline dicumarol containing two significantly different particle size populations could be deconvoluted solely based on their differences in 1H T 1 times. Relative populations of each particle size regime could also be approximated using two-component fitting models. Using NMR theory on spin diffusion as a reference, and taking into account the presence of crystal defects, a model for the correlation between the particle size of dicumarol and its 1H T 1 time was proposed.
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