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Article ; Online: Control of API release with matrix polymorphism in tristearin microspheres.

Pluntze, Amanda M / Cape, Jonathan L / Klaus, Nathaniel D / Lyon, David K

2023 Volume 636, Page(s) 122806

Abstract: Glycerides are widely employed as solid matrices in a range of pharmaceutical intermediates and dosage forms. Diffusion-based mechanisms are responsible for drug release, with both chemical and crystal polymorph differences in the solid lipid matrix ... ...

Abstract	Glycerides are widely employed as solid matrices in a range of pharmaceutical intermediates and dosage forms. Diffusion-based mechanisms are responsible for drug release, with both chemical and crystal polymorph differences in the solid lipid matrix cited as controlling factors in drug release rates. This work uses model formulations composed of crystalline caffeine embedded in tristearin to study the impacts to drug release from the two primary polymorphic states of tristearin and dependencies on the conversion routes between them. Using contact angles and NMR diffusometry, this work finds that drug release from the meta-stable α-polymorph is rate limited by a diffusive mechanism relating to its porosity and tortuosity, but initial burst release occurs due to ease of initial wetting. Poor wettability resulting from surface blooming can be rate limiting for the β-polymorph, resulting in slower initial drug release relative to the α-polymorph. The route to achieve the β-polymorph strongly impacts the bulk release profile due to differences in crystallite size and packing efficiency. API loading enhances the effective porosity, leading to enhanced drug release at high loadings. These findings offer generalizable principles to guide formulators on the types of impacts to drug release rates that one may expect due to triglyceride polymorphism.
MeSH term(s)	Microspheres ; Triglycerides/chemistry ; Drug Compounding/methods ; Glycerides
Chemical Substances	tristearin (P6OCJ2551R) ; Triglycerides ; Glycerides
Language	English
Publishing date	2023-03-07
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2023.122806
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Article: Correction: Adam et al. Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture.

Adam, Molly S / Miller, Warren K / Pluntze, Amanda M / Stewart, Aaron M / Cape, Jonathan L / Grass, Michael E / Morgen, Michael M

Pharmaceutics

2022 Volume 14, Issue 6

Abstract: ... Figure ... ...

Abstract	Figure Legend
Language	English
Publishing date	2022-06-09
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14061225
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Article: Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture.

Adam, Molly S / Miller, Warren K / Pluntze, Amanda M / Stewart, Aaron M / Cape, Jonathan L / Grass, Michael E / Morgen, Michael M

Pharmaceutics

2022 Volume 14, Issue 3

Abstract: Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the ... ...

Abstract	Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, many new chemical entities (NCEs) are poorly soluble not just in water, but in preferred organic spray drying solvents, e.g., methanol (MeOH) and acetone. Spraying poorly solvent soluble APIs from dilute solutions leads to low process throughput and small particles that challenge downstream processing. For APIs with basic p
Language	English
Publishing date	2022-03-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14030555
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Article ; Online: Mechanisms of water permeation and diffusive API release from stearyl alcohol and glyceryl behenate modified release matrices.

Cape, Jonathan L / Pluntze, Amanda M / Nelson, Madison L / Seymour, Joseph D / Miller, Warren K / Dower, April M / Buchanan, Stephanie S

International journal of pharmaceutics

2020 Volume 589, Page(s) 119819

Abstract: This work aims to develop complimentary analytical tools for lipid formulation selection that offer insights into the mechanisms of in-vitro drug release for solid lipid modified release excipients. Such tools are envisioned to aide and expedite the time ...

Abstract	This work aims to develop complimentary analytical tools for lipid formulation selection that offer insights into the mechanisms of in-vitro drug release for solid lipid modified release excipients. Such tools are envisioned to aide and expedite the time consuming process of formulation selection and development. Two pharmaceutically relevant solid lipid excipients are investigated, stearyl alcohol and glyceryl behenate, which are generally known to exhibit faster and slower relative release rates, respectively. Nuclear magnetic resonance spectroscopy and diffusometry are used, along with water uptake and dissolution experiments to help distinguish between two proposed in-vitro release mechanisms for crystalline caffeine from these matrices: 1) rate limiting movement of the wetting front through the particle, and 2) rate limiting diffusive release of the active from the wetted particle. Findings based on water permeation rates, API diffusion coefficients and kinetic modeling suggest that the rate limiting steps for caffeine release from these matrices are different, with stearyl alcohol being co-rate limited by movement of the wetting front and diffusive release of API, whereas glyceryl behenate is more strictly limited by diffusive release of API from the wetted matrix. A Peclet-like number is proposed to describe the different regimes of rate limitation for drug release. NMR spectroscopy and diffusometry are demonstrated to be useful tools for elucidating mechanisms of API release from crystalline drug/lipid mixtures and have significant potential value as screening tools in MR formulation development.
MeSH term(s)	Delayed-Action Preparations ; Fatty Acids ; Fatty Alcohols ; Solubility ; Water
Chemical Substances	Delayed-Action Preparations ; Fatty Acids ; Fatty Alcohols ; Water (059QF0KO0R) ; glyceryl behenate (18641-57-1) ; stearyl alcohol (2KR89I4H1Y)
Language	English
Publishing date	2020-08-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2020.119819
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Article ; Online: Water-Induced Phase Separation of Spray-Dried Amorphous Solid Dispersions.

Li, Na / Cape, Jonathan L / Mankani, Bharat R / Zemlyanov, Dmitry Y / Shepard, Kimberly B / Morgen, Michael M / Taylor, Lynne S

Molecular pharmaceutics

2020 Volume 17, Issue 10, Page(s) 4004–4017

Abstract: Spray drying is widely used in the manufacturing of amorphous solid dispersion (ASD) systems due to its fast drying rate, enabling kinetic trapping of the drug in amorphous form. Spray-drying conditions, such as solvent composition, can have a profound ... ...

Abstract	Spray drying is widely used in the manufacturing of amorphous solid dispersion (ASD) systems due to its fast drying rate, enabling kinetic trapping of the drug in amorphous form. Spray-drying conditions, such as solvent composition, can have a profound impact on the properties of spray-dried dispersions. In this study, the phase behavior of spray-dried dispersions from methanol and methanol-water mixtures was assessed using ritonavir and copovidone [poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA)] as dispersion components. The resultant ASDs were characterized using differential scanning calorimetry (DSC), fluorescence spectroscopy, X-ray photoelectron spectroscopy (XPS), as well as surface-normalized dissolution rate (SNDR) measurements. Quaternary phase diagrams were calculated using a four-component Flory-Huggins model. It was found that the addition of water to the solvent system can lead to phase separation during the spray-drying process. A 10:90 H
MeSH term(s)	Administration, Oral ; Chemistry, Pharmaceutical/methods ; Desiccation/methods ; Drug Compounding/methods ; Drug Liberation ; Solubility ; Solvents/chemistry ; Water/chemistry
Chemical Substances	Solvents ; Water (059QF0KO0R)
Language	English
Publishing date	2020-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.0c00798
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Article ; Online: Local Treatment of Non-small Cell Lung Cancer with a Spray-Dried Bevacizumab Formulation.

Shepard, Kimberly B / Vodak, David T / Kuehl, Philip J / Revelli, David / Zhou, Yue / Pluntze, Amanda M / Adam, Molly S / Oddo, Julia C / Switala, Lauren / Cape, Jonathan L / Baumann, John M / Banks, Michael

AAPS PharmSciTech

2021 Volume 22, Issue 7, Page(s) 230

Abstract: Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray ... ...

Abstract	Local delivery of biotherapeutics to the lung holds great promise for treatment of lung diseases, but development of physically stable, biologically active dry powder formulations of large molecules for inhalation has remained a challenge. Here, spray drying was used to manufacture a dry powder pulmonary formulation of bevacizumab, a monoclonal antibody approved to treat non-small cell lung cancer (NSCLC) by intravenous infusion. By reformulating bevacizumab for local delivery, reduced side effects, lower doses, and improved patient compliance are possible. The formulation had aerosol properties suitable for delivery to the deep lung, as well as good physical stability at ambient temperature for at least 6 months. Bevacizumab's anti-VEGF bioactivity was not impacted by the manufacturing process. The formulation was efficacious in an in vivo rat model for NSCLC at a 10-fold decrease in dose relative to the intravenous control.
MeSH term(s)	Administration, Inhalation ; Aerosols ; Animals ; Antineoplastic Agents, Immunological/administration & dosage ; Bevacizumab/administration & dosage ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Dry Powder Inhalers ; Lung Neoplasms/drug therapy ; Particle Size ; Powders ; Rats
Chemical Substances	Aerosols ; Antineoplastic Agents, Immunological ; Powders ; Bevacizumab (2S9ZZM9Q9V)
Language	English
Publishing date	2021-08-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2052070-0
ISSN	1530-9932 ; 1530-9932
ISSN (online)	1530-9932
ISSN	1530-9932
DOI	10.1208/s12249-021-02095-7
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Article ; Online: The role of nitrite ion in phagocyte function--perspectives and puzzles.

Cape, Jonathan L / Hurst, James K

Archives of biochemistry and biophysics

2009 Volume 484, Issue 2, Page(s) 190–196

Abstract: Macrophages and neutrophils are essential elements of host cellular defense systems that function, at least in part, by generating respiration-driven oxidative toxins in response to external stimuli. In both cells, encapsulation by phagocytosis provides ... ...

Abstract	Macrophages and neutrophils are essential elements of host cellular defense systems that function, at least in part, by generating respiration-driven oxidative toxins in response to external stimuli. In both cells, encapsulation by phagocytosis provides a mechanism to direct the toxins against the microbes. The toxic chemicals formed by these two phagocytic cells differ markedly, as do the enzymatic catalysts that generate them. Nitrite ion is microbicidal under certain conditions, is generated by activated macrophages, and is present at elevated concentration levels at infection sites. In this review, we consider potential roles that nitrite might play in cellular disinfection by these phagocytes within the context of available experimental information. Although the suggested roles are plausible, based upon the chemical and biochemical reactivity of NO2(-), studies to date provide little support for their implementation within phagosomes.
MeSH term(s)	Animals ; Bacteria/drug effects ; Cyclooxygenase 1/metabolism ; Cyclooxygenase 2/metabolism ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/physiology ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/physiology ; Macrophage Activation/physiology ; Macrophages/physiology ; Nitrites/metabolism ; Nitrites/pharmacology ; Oxidative Stress ; Phagocytes/drug effects ; Phagocytes/physiology ; Phagocytosis/physiology ; Phagosomes/drug effects ; Phagosomes/physiology
Chemical Substances	Nitrites ; Cyclooxygenase 1 (EC 1.14.99.1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; PTGS1 protein, human (EC 1.14.99.1)
Language	English
Publishing date	2009-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2009.01.010
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Article ; Online: Detection and mechanistic relevance of transient ligand radicals formed during [Ru(bpy)2(OH2)]2O4+-catalyzed water oxidation.

Cape, Jonathan L / Hurst, James K

Journal of the American Chemical Society

2008 Volume 130, Issue 3, Page(s) 827–829

Abstract: Mechanistic proposals to account for the reactivity of water-oxidizing ruthenium diimine complexes have often invoked participation of covalently hydrated or pseudobase intermediates formed by reaction of solvent with the polypyridyl ligands. Probing for ...

Abstract	Mechanistic proposals to account for the reactivity of water-oxidizing ruthenium diimine complexes have often invoked participation of covalently hydrated or pseudobase intermediates formed by reaction of solvent with the polypyridyl ligands. Probing for these intermediates has proven difficult because the concentrations of detectable reactive species are very low under commonly used experimental conditions. However, we have recently found that these transients accumulate in photocatalytic oxidation systems at neutral pH. In this work, we show that the reaction rates of these transient species correlate with catalytic activity and, therefore, that they meet minimal kinetic criteria to be true reaction intermediates.
Language	English
Publishing date	2008-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja077276s
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Article ; Online: Pathways of water oxidation catalyzed by ruthenium "blue dimers" characterized by 18O-isotopic labeling.

Cape, Jonathan L / Siems, William F / Hurst, James K

Inorganic chemistry

2009 Volume 48, Issue 18, Page(s) 8729–8735

Abstract: Earlier (18)O-H(2)O labeling studies had indicated that two concurrent pathways may exist for water oxidation catalyzed by [Ru(bpy)(2)(OH(2))](2)O(4+), a mu-oxo bridged diruthenium complex known colloquially as the "blue dimer". Specifically, the ... ...

Abstract	Earlier (18)O-H(2)O labeling studies had indicated that two concurrent pathways may exist for water oxidation catalyzed by [Ru(bpy)(2)(OH(2))](2)O(4+), a mu-oxo bridged diruthenium complex known colloquially as the "blue dimer". Specifically, the distribution of O(2) isotopomers obtained following its generation by the catalytically active form, [Ru(bpy)(2)(O)](2)(4+), suggested pathways in which either (1) one O atom was obtained from the terminally coordinated oxo atom and the second from the solvent or (2) both O atoms were obtained from the solvent. Plausible mechanisms have been advanced for the former pathway, but the second is enigmatic. In the present study, experiments are described that eliminate possibilities that the second pathway arises artifactually from rapid water exchange in reactive intermediary oxidation states of the catalyst, by mechanisms involving scrambling of the O(2) that is formed during reaction, or by mechanisms involving participation of the oxidant (Ce(4+) or S(2)O(8)(2-)). Comparative studies of partitioning between the two pathways made using catalysts containing substituted bipyridine ligands are consistent with a previously proposed pathway that involves noninnocent participation of these ligands.
Language	English
Publishing date	2009-09-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1484438-2
ISSN	1520-510X ; 0020-1669
ISSN (online)	1520-510X
ISSN	0020-1669
DOI	10.1021/ic900826q
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Article ; Online: Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

EClinicalMedicine

2023 Volume 66, Page(s) 102311

Abstract: Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective-but there has been no ... ...

Abstract	Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective-but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60-120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8-24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8-168 (i.e., weeks 2-24; range: 0-161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0-161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24-161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05-1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively-most commonly rapidly-resolving (mild-moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group-none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] -1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00-0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.
Language	English
Publishing date	2023-11-17
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2023.102311
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