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1.
Mol Pharm ; 17(7): 2232-2244, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32392068

RESUMO

Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

2.
Int J Pharm ; : 118897, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31836483

RESUMO

The Publisher regrets that this article is an accidental duplication of a published article,https://doi.org/10.1016/j.ijpx.2020.100041. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

3.
Mol Pharm ; 16(10): 4361-4371, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31436094

RESUMO

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API-polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

4.
Int J Pharm ; 554: 201-211, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30391338

RESUMO

Wet milling coupled with crystallisation has considerable potential to deliver enhanced control over particle attributes. The effect of process conditions and wet mill configuration on particle size, shape and surface energy has been investigated on acetaminophen using a seeded cooling crystallisation coupled with a wet mill unit generating size controlled acetaminophen crystals through an interchangeable rotor-tooth configuration. The integrated wet milling crystallisation platform incorporates inline focused beam reflectance measurement (FBRM) and particle vision measurement (PVM) for in-depth understanding of particle behaviour under high-shear conditions. We used a recently developed computational tool for converting chord length distribution (CLD) from FBRM to particle size distribution (PSD) to obtain quantitative insight into the effect of the competing mechanisms of size reduction and growth in a wet milling seeded crystallisation process for acetaminophen. The novelty of our wet milling crystallisation approach is in delivery of consistent surface energies across a range of particle sizes. This highlights the potential to engineer desirable particle attributes through a carefully designed, highly intensified crystallisation process.


Assuntos
Acetaminofen/administração & dosagem , Analgésicos não Entorpecentes/administração & dosagem , Química Farmacêutica/métodos , Tecnologia Farmacêutica/métodos , Acetaminofen/química , Analgésicos não Entorpecentes/química , Cristalização , Composição de Medicamentos/métodos , Tamanho da Partícula
5.
Annu Rev Chem Biomol Eng ; 9: 253-281, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29879381

RESUMO

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.


Assuntos
Preparações Farmacêuticas/química , Tecnologia Farmacêutica , Formas de Dosagem/normas , Indústria Farmacêutica , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/normas , Controle de Qualidade , Tecnologia Farmacêutica/normas
6.
J Chem Inf Model ; 57(8): 1807-1815, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28666389

RESUMO

Reported here is a rational approach for the selection of solvents intended for use in physical form screening based on a novel chemoinformatics analysis of solvent properties. A comprehensive assessment of eight clustering methods was carried out on a series of 94 solvents described by calculated molecular descriptors using the clusterSim package in R. The effectiveness of clustering methods was evaluated using a range of statistical measures as well as increasing efficiency of solid form discovery using a cluster-based solvent selection approach. Multidimensional scaling was used to illustrate cluster analysis on a two-dimensional solvent map. The map presented here is a valuable tool to aid efficient solvent selection in physical form screens. This tool is equally applicable to any scientific area which requires a solubility dependent decision on solvent choice.


Assuntos
Informática/métodos , Bibliotecas de Moléculas Pequenas/química , Solventes/química , Modelos Moleculares , Conformação Molecular
7.
J Pharm Sci ; 106(7): 1874-1880, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28431966

RESUMO

Carbamazepine (CBZ) is an active pharmaceutical ingredient used in the treatment of epilepsy that can form at least 5 polymorphic forms. Metastable form IV was originally discovered from crystallization with polymer additives; however, it has not been observed from subsequent solvent-only crystallization efforts. This work reports the reproducible formation of phase pure crystalline form IV by spray drying of methanolic CBZ solution. Characterization of the material was carried out using diffraction, scanning electron microscopy, and differential scanning calorimetry. In situ Raman spectroscopy was used to monitor the spray-dried product during the spray drying process. This work demonstrates that spray drying provides a robust method for the production of form IV CBZ, and the combination of high supersaturation and rapid solid isolation from solution overcomes the apparent limitation of more traditional solution crystallization approaches to produce metastable crystalline forms.


Assuntos
Anticonvulsivantes/química , Carbamazepina/química , Dessecação/métodos , Estabilidade de Medicamentos , Cristalização , Difração de Pó , Solubilidade , Análise Espectral Raman , Difração de Raios X
8.
Chem Commun (Camb) ; 52(46): 7384-6, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27193234

RESUMO

A new method of inducing the crystallisation of metastable polymorphs by isomorphous templating has been developed and used to reproduce the crystallisation of CBZ-V on the surface of DHC-II. Studies of the growth of CBZ-V on DHC-II single crystals show crystals growing laterally and vertically on DHC-II surfaces without any significant face selectivity. The generality of this computationally inspired crystallisation approach is demonstrated by producing the first crystals of an entirely new polymorph of cyheptamide, which is isomorphous to both DHC-II and CBZ-V.

9.
Acta Crystallogr E Crystallogr Commun ; 72(Pt 1): 53-5, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26870584

RESUMO

The title 1:1 co-crystal, C11H14O3·C6H6N2O [systematic name: butyl 4-hy-droxy-benzoate-isonicotinamide (1/1)], crystallizes with one mol-ecule of butyl-paraben (BPN) and one mol-ecule of isonicotinamide (ISN) in the asymmetric unit. In the crystal, BPN and ISN mol-ecules form hydrogen-bonded (O-H⋯N and N-H⋯O) dimers of paired BPN and ISN mol-ecules. These dimers are further connected to each other via N-H⋯O=C hydrogen bonds, creating ribbons in [011] which further stack along the a axis to form a layered structure with short C⋯C contacts of 3.285 (3) Å. Packing inter-actions within the crystal structure were assessed using PIXEL calculations.

10.
Acta Crystallogr E Crystallogr Commun ; 71(Pt 2): 139-41, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25878802

RESUMO

The mixed solvated salt 4-(2-chloro-dibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-ium acetate-acetic acid-cyclo-hexane (2/2/1), C17H17ClN3O(+)·C2H3O2 (-)·C2H4O2·0.5C6H12, crystallizes with one mol-ecule of protonated amoxapine (AXPN), an acetate anion and a mol-ecule of acetic acid together with half a mol-ecule of cyclo-hexane. In the centrosymmetric crystal, both enanti-omers of the protonated AXPN mol-ecule stack alternatively along [001]. Acetate anions connect the AXPN cations through N-H⋯O hydrogen bonding in the [010] direction, creating a sheet lying parallel to (100). The acetic acid mol-ecules are linked to the acetate anions via O-H⋯O hydrogen bonds within the sheets. Within the sheets there are also a number of C-H⋯O hydrogen bonds present. The cyclo-hexane solvent mol-ecules occupy the space between the sheets.

11.
J Pharm Sci ; 104(3): 781-791, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28756840

RESUMO

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are.

12.
J Pharm Sci ; 104(3): 781-91, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25470351

RESUMO

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are: Develop flow chemistry toolboxes, exploiting the advantages of flow processing and including highly selective chemistries that allow use of simple and effective continuous workup technologies. Availability of modular or plug and play type equipment especially for workup to assist in straightforward deployment in the laboratory. As with learning from other industries, standardization is highly desirable and will require cooperation across industry and academia to develop and implement. Implement and exploit process analytical technologies (PAT) for real-time dynamic control of continuous processes. Develop modeling and simulation techniques to support continuous process development and control. Progress is required in multiphase systems such as crystallization. Involve all parts of the organization from discovery, research and development, and manufacturing in the implementation of CM. Engage with academia to develop the training provision to support the skills base for CM, particularly in flow chemistry, physical chemistry, and chemical engineering skills at the chemistry-process interface. Promote and encourage publication and dissemination of examples of CM across the sector to demonstrate capability, engage with regulatory comment, and establish benchmarks for performance and highlight challenges. Develop the economic case for CM of drug substance. This will involve various stakeholders at project and business level, however establishing the critical economic drivers is critical to driving the transformation in manufacturing.


Assuntos
Indústria Farmacêutica/métodos , Preparações Farmacêuticas/síntese química , Tecnologia Farmacêutica/métodos , Fluxo de Trabalho , Automação , Química Farmacêutica , Comportamento Cooperativo , Cristalização , Indústria Farmacêutica/instrumentação , Indústria Farmacêutica/normas , Indústria Farmacêutica/tendências , Desenho de Equipamento , Humanos , Comunicação Interdisciplinar , Cultura Organizacional , Preparações Farmacêuticas/normas , Controle de Qualidade , Tecnologia Farmacêutica/instrumentação , Tecnologia Farmacêutica/normas , Tecnologia Farmacêutica/tendências
13.
Acta Crystallogr C ; 69(Pt 11): 1273-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24192171

RESUMO

The crystal structures of loxapine succinate [systematic name: 4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-1-methylpiperazin-1-ium 3-carboxypropanoate], C18H19ClN3O(+)·C4H5O4(-), and loxapine succinate monohydrate {systematic name: bis[4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-1-methylpiperazin-1-ium] succinate succinic acid dihydrate}, 2C18H19ClN3O(+)·C4H4O4(2-)·C4H6O4·2H2O, have been determined using X-ray powder diffraction and single-crystal X-ray diffraction, respectively. Fixed cell geometry optimization calculations using density functional theory confirmed that the global optimum powder diffraction derived structure also matches an energy minimum structure. The energy calculations proved to be an effective tool in locating the positions of the H atoms reliably and verifying the salt configuration of the structure determined from powder data. Crystal packing analysis of these structures revealed that the loxapine succinate structure is based on chains of protonated loxapine molecules while the monohydrate contains dispersion stabilized centrosymmetric dimers. Incorporation of water molecules within the crystal lattice significantly alters the molecular packing and protonation state of the succinic acid.


Assuntos
Loxapina/química , Água/química , Computadores Moleculares , Estrutura Molecular , Difração de Pó , Difração de Raios X
14.
Cryst Growth Des ; 13(9): 4071-4083, 2013 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-24027438

RESUMO

The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at aw (water activity) = 0.15 at 25 °C. Structures have been derived from single crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher energy structure on a computationally generated crystal energy landscape, which has the anhydrate crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)sorption, and thermo-analytical methods with the computationally generated crystal energy landscape and lattice energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two monotropically related dimethyl sulfoxide monosolvates were found in the accompanying solid form screen.

15.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 5): o752-3, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23723900

RESUMO

In the title solvate, C17H20N4S·2C3H8O, pairs of olanzapine mol-ecules related by a centre of inversion stack along the a axis, forming columns, which are packed parallel to each other along the b axis, forming a sheet arrangement. The columns within these sheets are hydrogen bonded to each other through the propan-2-ol solvent mol-ecules. The diazepine ring of the olanzapine exists in a puckered conformation with the thiophene and phenyl rings making a dihedral angle of 57.66 (7)° and the piperazine ring adopts a chair conformation with the methyl group in an equatorial position.

16.
Cryst Growth Des ; 13(1): 19-23, 2013 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-23378823

RESUMO

We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity.

18.
ACS Comb Sci ; 14(3): 155-9, 2012 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-22332944

RESUMO

Reported here is a relatively simple technique for polymorph screening of pharmaceutical compounds that are thermally stable. Polymer libraries have previously been used as surfaces to influence, or direct, the crystalline form adopted by an active pharmaceutical ingredient on crystallization from solution. In this current work, we demonstrate the polymorph-directing effect of homopolymer surfaces in the absence of solvent by recrystallization from the supercooled melt. When the nonsteroidal anti-inflammatory drug indomethacin is melted, cooled, and subsequently reheated above its glass transition temperature on an untreated surface, it has a proclivity to crystallize as its δ polymorph. On certain polymer surfaces, however, it preferentially crystallizes as the α polymorph, as a direct result of polymer templating. The method is well-suited to implementation in multiwell plate formats requiring only small amounts of material and enabling multiple experiments to be carried out in parallel with samples readily characterized using X-ray powder diffraction.


Assuntos
Cristalização , Indometacina/química , Polímeros/química , Anti-Inflamatórios não Esteroides/química , Temperatura Baixa , Vidro/química , Estrutura Molecular
19.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 12): o3377, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23476209

RESUMO

The title co-crystal, C4H7N5·C4H10O2, crystallizes with one mol-ecule of 6-methyl-1,3,5-triazine-2,4-diamine (DMT) and one mol-ecule of butane-1,4-diol in the asymmetric unit. The DMT mol-ecules form ribbons involving centrosymmetric R2(2)(8) dimer motifs between DMT mol-ecules along the c-axis direction. These ribbons are further hydrogen bonded to each other through butane-1,4-diol, forming sheets parallel to (121).

20.
Chem Commun (Camb) ; 47(34): 9627-9, 2011 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-21796276

RESUMO

High-resolution STM imaging of the structures formed by carbamazepine molecules adsorbed onto a pseudo-ordered carbamazepine monolayer on Au(111) shows the formation of previously unreported 1-dimensional supramolecular assemblies.


Assuntos
Carbamazepina/química , Adsorção , Técnicas de Química Sintética , Ouro/química , Temperatura
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