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1.
Pharmaceutics ; 15(2)2023 Feb 10.
Article in English | MEDLINE | ID: mdl-36839916

ABSTRACT

Compressed mini-tablets in sachets or capsules are an increasingly prevalent oral solid dosage form for pediatric products. While resembling adult tablets, additional care is required to control weight and potency (blend uniformity) variation due to their small size (≤2.5 mm average diameter). Additionally, sachet fill count errors complicate dose accuracy as they are difficult to resolve with weight-checking equipment. This study quantified the probability of failing content uniformity (CU) specifications (which results in the inability to release a batch) defined in USP <905> using a Monte Carlo computational model. Failure risk was modeled as a function of sachet fill count, mini-tablet weight, potency distribution, and fill error frequency. The model allows product developers to (1) determine appropriate fill counts based on anticipated product weight and potency relative standard deviation (RSD), (2) set fill error probability tolerances for sachet filling processes, (3) identify CU improvement opportunities, and (4) quantify the probability of CU failure informing risk management activities and risk disclosure for regulatory agencies. A representative product with weight and potency RSD no greater than 5%, fill count of 1-4 mini-tablets per sachet, and fill error probability per mini-tablet filled of 0.1% may experience CU batch failure probabilities as high as 8.23%, but only 0.283% if the fill count is increased to 5-10 mini-tablets per sachet. Generally, fill counts of less than five mini-tablets per sachet should be avoided where possible.

2.
J Pharm Sci ; 112(8): 2057-2068, 2023 Aug.
Article in English | MEDLINE | ID: mdl-36574837

ABSTRACT

Co-precipitation is an emerging manufacturing strategy for amorphous solid dispersions (ASDs). Herein, the interplay between processing conditions, surface composition, and release performance was evaluated using grazoprevir and hypromellose acetate succinate as the model drug and polymer, respectively. Co-precipitated amorphous dispersion (cPAD) particles were produced in the presence and absence of an additional polymer that was either dissolved or dispersed in the anti-solvent. This additional polymer in the anti-solvent was deposited on the surfaces of the cPAD particles during isolation and drying to create hierarchical particles, which we define here as a core ASD particle with an additional water soluble component that is coating the particle surfaces. The resultant hierarchical particles were characterized using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and X-ray photoelectron spectroscopy (XPS). Release performance was evaluated using a two-stage dissolution test. XPS analysis revealed a trend whereby cPAD particles with a lower surface drug concentration showed improved release relative to particles with a higher surface drug concentration, for nominally similar drug loadings. This surface drug concentration could be impacted by whether the secondary polymer was dissolved in the anti-solvent or dispersed in the anti-solvent prior to isolating final dried hierarchical cPAD powders. Grazoprevir exposure in dogs was higher when the hierarchical cPAD was dosed, with ∼1.8 fold increase in AUC compared to the binary cPAD. These observations highlight the important interplay between processing conditions and ASD performance in the context of cPAD particles and illustrate a hierarchical particle design as a successful approach to alter ASD surface chemistry to improve dissolution performance.


Subject(s)
Cyclopropanes , Polymers , Animals , Dogs , Solubility , Drug Compounding/methods , Polymers/chemistry , Solvents , Drug Liberation
3.
Expert Opin Drug Deliv ; 18(5): 577-593, 2021 05.
Article in English | MEDLINE | ID: mdl-33275066

ABSTRACT

Introduction: Drug eluting implants offer patient convenience and improved compliance through less frequent dosing, eliminating repeated, painful injections and providing localized, site specific delivery with applications in contraception, ophthalmology, and oncology.Areas covered: This review provides an overview of available implant products, design approaches, biodegradable and non-biodegradable polymeric materials, and fabrication techniques with a focus on commercial applications and industrial drug product development. Developing trends in the field, including expanded availability of suitable excipients, development of novel materials, scaled down manufacturing process, and a wider understanding of the implant development process are discussed and point to opportunities for differentiated drug eluting implant products.Expert opinion: In the future, long-acting implants will be important clinical tools for prophylaxis and treatment of global health challenges, especially for infectious diseases, to reduce the cost and difficulty of treating chronic indications, and to prolong local delivery in difficult to administer parts of the body. These products will help improve patient safety, adherence, and comfort.


Subject(s)
Drug Delivery Systems , Pharmaceutical Preparations , Drug Development , Drug Implants , Excipients , Humans
4.
Mol Pharm ; 17(8): 2789-2808, 2020 08 03.
Article in English | MEDLINE | ID: mdl-32520562

ABSTRACT

Oral delivery of poorly water-soluble, weakly basic drugs may be problematic based on the drugs' intrinsic properties. Many drugs in this subset have overcome barriers to delivery following successful formulation as amorphous solid dispersions (ASDs). To process drugs as ASDs, multiple commercially relevant technologies have been developed and become well understood. However, ASD-producing technologies like spray drying and KinetiSol produce ASDs with vastly differing particle characteristics. Ultimately, the objective of this study was to assess whether processing an ASD of identical composition utilizing two different ASD-producing technologies (KinetiSol and spray drying) may impact the oral bioavailability of a weakly basic drug. For this study, we selected a weakly basic drug (Boehringer Ingelheim research compound 639667, BI 667) and processed it with an anionic polymer (hypromellose acetate succinate MMP grade (HPMCAS-MMP)) to evaluate whether the processing technology could modulate drug release in acidic and neutral media. Multiple characterization techniques (specific surface area (SSA), particle size distribution (PSD), scanning electron microscopy (SEM)) were utilized to evaluate the surface characteristics and differences in particles produced by KinetiSol and spray drying. Molecular interactions and drug-polymer miscibility of the processed particles were assessed using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance, respectively. In vitro nonsink, pH-shift dissolution in biorelevant media and dissolution/permeation studies were conducted to better understand the release of BI 667 based on processing technology and particle size distribution. Finally, an in vivo male Beagle dog study was conducted to assess the impact of processing technology on oral bioavailability. In this study, we demonstrate that particles produced by KinetiSol have enhanced oral bioavailability compared with spray-dried particles when delivering a weakly basic drug processed with an anionic polymer. The findings of this study demonstrate that by utilizing KinetiSol, drug release may be controlled such that supersaturation in acidic media is inhibited and supersaturation of the drug is designed to occur in neutral media, ultimately enhancing oral bioavailability.


Subject(s)
Pharmaceutical Preparations/chemistry , Polymers/chemistry , Animals , Chemistry, Pharmaceutical/methods , Dogs , Drug Carriers/chemistry , Drug Compounding/methods , Drug Liberation/drug effects , Male , Solubility/drug effects , Water/chemistry
5.
Mol Pharm ; 17(7): 2585-2598, 2020 07 06.
Article in English | MEDLINE | ID: mdl-32401529

ABSTRACT

Despite the wide utilization of amorphous solid dispersions (ASDs) for formulating poorly water-soluble drugs, fundamental understanding of the structural basis behind their stability and dissolution behavior is limited. This is largely due to the lack of high-resolution structural tools for investigating multicomponent and amorphous systems in the solid state. In this study, we present what is likely the first publication quantifying the molecular interaction between the drug and polymer in ASDs at an angstrom level by utilizing 19F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the 19F-13C rotational-echo and double-resonance (REDOR) technique was developed to quantify interatomic distances by implementing a supercycled symmetry-based recoupling schedule and synchronized simultaneous detection. We successfully deployed the technique to identify "head-to-head" and "head-to-tail" packing of crystalline posaconazole (POSA). To probe molecular interactions between POSA and hypromellose acetate succinate (HPMCAS) in the dispersion, as a major goal of this study, two-dimensional (2D) 1H-19F correlation experiments were performed. The approach facilitated observation of intermolecular hydrogen-to-fluorine contacts between the hydroxyl group of the polymer and the difluorophenyl group of the drug substance. Atomic distance measurement, utilizing the developed 19F-13C REDOR technique, revealed the close proximity of 13COH-19F at 4.3 Å. Numerical modeling analysis suggested a possible hydrogen bonding interaction between the polymer O-H group as an acceptor and POSA fluorine (O-H···F) or difluorophenyl ring (O-H···Ph) as a donor. These 19F MAS NMR techniques, including 2D 19F-1H heteronuclear correlation and 19F-13C atomic distance measurement, may shed light on the nature (i.e., type and strength) of drug-polymer interactions in ASDs and offer a new high-resolution analytical protocol for probing the microstructure of amorphous pharmaceutical materials.


Subject(s)
Magnetic Resonance Spectroscopy/methods , Methylcellulose/analogs & derivatives , Polymers/chemistry , Triazoles/chemistry , Hydrogen Bonding , Methylcellulose/chemistry , Models, Molecular , Molecular Structure
6.
Pharmaceutics ; 12(4)2020 Apr 20.
Article in English | MEDLINE | ID: mdl-32326114

ABSTRACT

Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs are normally obtained with high processing temperatures and mechanical stress. Interestingly, one-third of pharmaceutical compounds reportedly exist in hydrate forms. In this study, we selected carbamazepine (CBZ) dihydrate to investigate its solid-state changes during the dehydration process and the impact of the dehydration on the preparation of CBZ ASDs using a Leistritz micro-18 extruder. Various characterization techniques were used to study the dehydration kinetics of CBZ dihydrate under different conditions. We designed the extrusion runs and demonstrated that: 1) the dehydration of CBZ dihydrate resulted in a disordered state of the drug molecule; 2) the resulted higher energy state CBZ facilitated the drug solubilization and mixing with the polymer matrix during the HME process, which significantly decreased the required extrusion temperature from 140 to 60 °C for CBZ ASDs manufacturing compared to directly processing anhydrous crystalline CBZ. This work illustrated that the proper utilization of drug hydrates can significantly improve the processability of HME for preparing ASDs.

7.
J Pharm Sci ; 109(6): 1967-1977, 2020 06.
Article in English | MEDLINE | ID: mdl-32087181

ABSTRACT

Acyclovir is a poorly permeable, short half-life drug with poor colonic absorption, and current conventional controlled release formulations are unable to decrease the frequency of administration. We designed acyclovir dosage forms to be administered less frequently by being retained in the stomach and releasing drug over an extended duration. We developed a conventional modified-release matrix tablet to sustain the release of acyclovir and surrounded it with a hydrophilic poly(urethane) layer. When hydrated, the porous poly(urethane) swells to a size near or beyond that of the relaxed pylorus diameter and does not affect drug release rate. We demonstrated that the formulation is retained in the stomach for extended durations as it slowly releases drug, allowing for similar area under the curve but delayed tmax relative to a nongastroretentive control tablet. Unlike many other gastroretentive formulations, this dosage form design decouples drug release rate from gastric retention time, allowing them to be modulated independently. It also effectively retains in the stomach regardless of the prandial state, differentiating from other approaches. Our direct observation of excised rat stomachs allowed for a rigorous assessment of the impact of polymer swelling extent and the prandial state on both the dosage form integrity and retention time.


Subject(s)
Drug Delivery Systems , Urethane , Administration, Oral , Biological Availability , Delayed-Action Preparations , Drug Liberation , Tablets
8.
Int J Pharm ; 568: 118550, 2019 Sep 10.
Article in English | MEDLINE | ID: mdl-31336152

ABSTRACT

Implants offer the opportunity to improve patient adherence and real-world outcomes. However, most polymers used today are hydrophobic and limit drug properties suitable for development. Thermoplastic poly(urethanes) (TPUs) form pores upon hydration and may facilitate the development of implants containing drugs exhibiting broadly different properties. We sought to investigate the effect of drug physicochemical properties on permeability through membranes of varying TPU mixture composition; leverage imaging to visualize microstructural changes to the membrane across the TPU mixture composition range; and quantitatively characterize the membrane microstructure using equivalent pore analysis. We observed a correlation between drug hydrophobicity and its permeability through hydrophobic-rich TPU membranes. Conversely, all compounds diffused through hydrophilic-rich TPU membranes at similar rates, regardless of drug properties. Imaging revealed significant microstructure differences between hydrophobic-rich and hydrophilic-rich TPU membranes, supporting hypotheses proposed in our previous study. The hydrated hydrophilic TPU membrane pore area was determined to be 0.583% and its equivalent pore radius was found to be 128 nm, suggesting that hydrophilic TPU membranes may be used to modify the release of small molecular weight drugs and macromolecules. These findings highlight the benefits of hydrophilic TPUs as rate-controlling membranes to modulate the release rate of drugs with varying physicochemical properties.


Subject(s)
Membranes, Artificial , Polyurethanes/chemistry , Dextrans/chemistry , Diffusion , Drug Implants , Emtricitabine/chemistry , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/chemistry , Hydrophobic and Hydrophilic Interactions , Ibuprofen/chemistry , Metoprolol/chemistry , Molecular Weight , Permeability , Porosity
9.
Mol Pharm ; 16(6): 2579-2589, 2019 06 03.
Article in English | MEDLINE | ID: mdl-31021639

ABSTRACT

Molecular interactions between the active pharmaceutical ingredient and polymer have potentially substantial impacts on the physical stability of amorphous solid dispersions (ASDs), presumably by manipulating molecular mobility and miscibility. However, structural details for understanding the nature of the molecular contacts and mechanistic roles in various physicochemical and thermodynamic events often remain unclear. This study provides a spectroscopic characterization of posaconazole (POSA) formulations, a second-generation triazole antifungal drug (Noxafil, Merck & Co., Inc., Kenilworth, NJ, USA), at molecular resolution. One- and two-dimensional (2D) solid-state NMR (ssNMR) techniques including spectral editing, heteronuclear 1H-13C, 19F-13C, 15N-13C, and 19F-1H polarization transfer, and spin correlation and ultrafast magic angle spinning, together with the isotopic labeling strategy, were utilized to uncover molecular details in POSA ASDs in a site-specific manner. Active groups in triazole and difluorophenyl rings exhibited rich but distinct categories of interactions with two polymers, hypromellose acetate succinate and hypromellose phthalate, including intermolecular O-H···O═C and O-H···F-C hydrogen bonding, π-π aromatic packing, and electrostatic interaction. Interestingly, the chlorine-to-fluorine substituent in POSA, one of the major structural differences from itraconazole that could facilitate binding to the biological target, offers an additional contact with the polymer. These findings exhibit 2D ssNMR as a sensitive technique for probing sub-nanometer structures of pharmaceutical materials and provide a structural basis for optimizing the type and strength of drug-polymer interactions in the design of amorphous formulations.


Subject(s)
Carbon/chemistry , Colloids/chemistry , Triazoles/chemistry , Hydrogen Bonding , Magnetic Resonance Spectroscopy
10.
Int J Pharm ; 561: 324-334, 2019 Apr 20.
Article in English | MEDLINE | ID: mdl-30858115

ABSTRACT

Hot melt extrusion (HME) has been used to prepare solid dispersions, especially molecularly dispersed amorphous solid dispersions (ASDs) for solubility enhancement purposes. The energy generated by the extruder in the form of mechanical and thermal output enables the dispersion and dissolution of crystalline drugs in polymeric carriers. However, the impact of this thermal and mechanical energy on ASD systems remains unclear. We selected a model ASD system containing nifedipine (NIF) and polyvinylpyrrolidone vinyl acetate (PVP/VA 64) to investigate how different types of energy input affect the preparation and physical stability of ASDs. Formulations were prepared using a Leistritz Nano-16 extruder, and we varied the screw design, barrel temperature, screw speed, and feed rate to control the mechanical and thermal energy input. Specific mechanical energy (SME) was calculated to quantitate the mechanical energy input, and the thermal energy was estimated using barrel temperature. We find that both mechanical and thermal energy inputs affect the conversion of crystalline NIF into an amorphous form, and they also affect the level of mixing and the degree of homogeneity in NIF ASDs. However, for small size extruders (e.g., Leistritz Nano-16), thermal energy is more efficient than mechanical energy in preparing NIF ASDs that have better stability.


Subject(s)
Drug Carriers/chemistry , Drug Compounding/methods , Drug Stability , Hot Temperature , Mechanical Phenomena , Nifedipine/chemistry , Povidone/chemistry , Vinyl Compounds/chemistry , Solubility
11.
Int J Pharm ; 557: 390-401, 2019 Feb 25.
Article in English | MEDLINE | ID: mdl-30529658

ABSTRACT

Hydrophobic and hydrophilic thermoplastic poly(urethane) (TPU) mixtures offer the opportunity to tune water swelling capacity and diffusion rate for drugs exhibiting broadly different properties. We sought to (1) assess the range of drug diffusion rates achieved by varying hydrophilic-to-hydrophobic TPU ratio relative to varying ethylene vinyl acetate (EVA) crystallinity; (2) investigate the effect of mixture ratio on permeability of emtricitabine; and (3) investigate the impact of the extrusion process on mixing of the two TPUs and the resulting impact on drug diffusion. The permeability of water-soluble emtricitabine exhibited a 736-fold range across the blends of TPU, but only a 3.4-fold range across the EVA grades investigated. Varying hydrophilic content of the TPU mixture from 0% to 25% (w/w) led to a negligible permeability change, while changing hydrophilic content from 55% to 100% resulted in a linear 3-fold increase in drug permeability. Interestingly, an 123-fold permeability change occurred between 50% and 55% hydrophilic polymer. Extrusion process parameters exhibited minimal impact on homogeneity and drug diffusion. These findings suggest that hydrophilic polymer domains form a continuous network at levels above 55% hydrophilic TPU, thus facilitating a water-filled porous network when exposed to water that provides a mechanism for accelerated drug diffusion.


Subject(s)
Anti-HIV Agents/chemistry , Drug Implants , Emtricitabine/chemistry , Polyurethanes/chemistry , Polyvinyls/chemistry , Reverse Transcriptase Inhibitors/chemistry , Delayed-Action Preparations/chemistry , Drug Liberation , Hydrophobic and Hydrophilic Interactions
12.
Pharmaceutics ; 10(2)2018 May 09.
Article in English | MEDLINE | ID: mdl-29747409

ABSTRACT

Since their introduction over 50 years ago, polyurethanes have been applied to nearly every industry. This review describes applications of polyurethanes to the development of modified release drug delivery. Although drug delivery research leveraging polyurethanes has been ongoing for decades, there has been renewed and substantial interest in the field in recent years. The chemistry of polyurethanes and the mechanisms of drug release from sustained release dosage forms are briefly reviewed. Studies to assess the impact of intrinsic drug properties on release from polyurethane-based formulations are considered. The impact of hydrophilic water swelling polyurethanes on drug diffusivity and release rate is discussed. The role of pore formers in modulating drug release rate is examined. Finally, the value of assessing mechanical properties of the dosage form and approaches taken in the literature are described.

13.
Biomaterials ; 30(26): 4336-47, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19481253

ABSTRACT

Here we demonstrate the use of a twin screw extrusion/spiral winding (TSESW) process to generate protein-encapsulated tissue engineering scaffolds. Bovine serum albumin (BSA) was distributed into PCL matrix using both wet and hot melt extrusion methods. The encapsulation efficiency and the time-dependent release rate, as well as the tertiary structure of BSA (via circular dichroism), were investigated as a function of processing method and conditions. Within the relatively narrow processing window of this demonstration study it was determined that the wet extrusion method gave rise to greater stability of the BSA on the basis of circular dichroism data. The rate of proliferation of human fetal osteoblast (hFOB) cells and the rate of mineral deposition were found to be greater for wet extruded scaffolds, presumably due to the important differences in surface topographies (smoother scaffold surfaces upon wet extrusion). Overall, these findings suggest that the twin screw extrusion/spiral winding (TSESW) process offers significant advantages and flexibility in generating a wide variety of non-cytotoxic tissue engineering scaffolds with controllable distributions of porosity, physical and chemical properties and protein concentrations that can be tailored for the specific requirements of each tissue engineering application.


Subject(s)
Polyesters/chemistry , Serum Albumin, Bovine/metabolism , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Alkaline Phosphatase/metabolism , Animals , Cattle , Cell Adhesion , Circular Dichroism , Humans , Microscopy, Electron, Scanning , Osteoblasts/cytology , Osteoblasts/enzymology , Osteoblasts/ultrastructure , Porosity , Protein Stability , Protein Structure, Secondary , Serum Albumin, Bovine/chemistry , Time Factors
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