One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability

Clawson, Jacalyn S.; Kennedy-Gabb, Sonya; Lee, Alfred Y.; Copley, Royston C. B.

doi:10.1002/jps.22621

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…Relatively small changes (i.e., changes in bond angle and/or bond distance) will result in variations to the chemical shift, leading to a chemical shift distribution, observed as inhomogeneous broadening to the spectrum. Such a broadening effect is illustrated in Figure 2 by an NMR investigation of stepwise morphology change (“crystalline” to “crystalline with site disorder” to “amorphous”) in a drug molecule system, adapted from work by Clawson et al [ 12 ]. Figure 2 a shows a 13 C CP MAS spectrum of a crystalline powder sample formed by mixing the drug molecule I in base A (tartaric acid) in a 1: 1 ratio, where the molecular structures are illustrated on top of the figure.…”

Section: Nmr Detection Of Spin-1/2 Nuclei In Disordered Environmenmentioning

confidence: 99%

“…Solid state NMR is a complementary method that can provide local structural information at the atomic level without the requirement of the long-range order and periodicity. Material structures can be characterized in two different regimes in solid-state NMR, namely, spectroscopy [2,12,13] and relaxometry [3,4,14]. In particular, the former refers to the spectral analysis such as chemicals shift, lineshape and linewidth, while the latter consists of measurements of nuclear relaxation times [14].…”

Section: Introductionmentioning

confidence: 99%

“…The material in crystalline (a), crystalline with site disorder (b) and amorphous (c) forms were prepared by mixing I with A or B at ratios indicated in each figure. Reprinted from Ref [12],. Copyright (2011), with permission from Elsevier.…”

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confidence: 99%

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A Practical Review of NMR Lineshapes for Spin-1/2 and Quadrupolar Nuclei in Disordered Materials

Chen

2020

IJMS

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NMR is a powerful spectroscopic method that can provide information on the structural disorder in solids, complementing scattering and diffraction techniques. The structural disorder in solids can generate a dispersion of local magnetic and electric fields, resulting in a distribution of isotropic chemical shift δiso and quadrupolar coupling CQ. For spin-1/2 nuclei, the NMR linewidth and shape under high-resolution magic-angle spinning (MAS) reflects the distributions of isotropic chemical shift, providing a rich source of disorder information. For quadrupolar nuclei, the second-order quadrupolar broadening remains present even under MAS. In addition to isotropic chemical shift, structural disorder can impact the electric field gradient (EFG) and consequently the quadrupolar NMR parameters. The distributions of quadrupolar coupling and isotropic chemical shift are superimposed with the second-order quadrupolar broadening, but can be potentially characterized by MQMAS (multiple-quantum magic-angle spinning) spectroscopy. We review analyses of NMR lineshapes in 2D DQ–SQ (double-quantum single-quantum) and MQMAS spectroscopies, to provide a guide for more general lineshape analysis. In addition, methods to enhance the spectral resolution and sensitivity for quadrupolar nuclei are discussed, including NMR pulse techniques and the application of high magnetic fields. The role of magnetic field strength and its impact on the strategy of determining optimum NMR methods for disorder characterization are also discussed.

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Section: Nmr Detection Of Spin-1/2 Nuclei In Disordered Environmenmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Practical Review of NMR Lineshapes for Spin-1/2 and Quadrupolar Nuclei in Disordered Materials

Chen

2020

IJMS

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“…While the financial drivers may present the biggest case for avoiding dry milling, potential disorder in the milled crystalline material − that is driven by the shear and tensile strength stresses associated with dry milling can be another driver to avoid dry milling. Milling-induced disorder can span a spectrum from the formation of second phase amorphous material, to the exposure of higher energy crystal faces, to lattice disorder or conformational defects. , This disorder, or bulk exposure of higher energy surfaces, can have detrimental impacts on API physical properties including flow, dissolution, and stability, among others. Additionally, the nature of the defects of milled material is complex, with the comparability of these milling induced defects to crystallization induced defects (i.e., those brought about via melt quenching, or other forms of process induced disorder) is generally unknown …”

Section: Introductionmentioning

confidence: 99%

High-Shear Rotor–Stator Wet Milling for Drug Substances: Expanding Capability with Improved Scalability

Harter

Schenck

Lee

et al. 2013

Org. Process Res. Dev.

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Rotor−stator wet mills are commonly used in the pharmaceutical industry to reduce particle size and normalize API physical properties as a means to facilitate downstream drug product operations and/or achieve targeted in vivo product performance. Wet milling is robust, relatively easy to use, broadly applicable, and offers both financial and API physical property advantages over dry milling. Historical rotor−stator wet mill technologies are generally capable of achieving particles sizes down to ∼25 μm. Newer high-shear wet mills allow for a reduction of particle size down to ∼10−15 μm. In addition to the improved particle size reduction, recent wet mill designs better maintain geometric consistency across the product line, thereby providing enhanced scalability. A traditional scale-up approach for wet milling involved maintaining the tip speed of the rotor (assuming constant shear gap and thus constant shear rate) and would generally allow comparable terminal particle size (that near steadystate particle size where particle size reduction drastically slows) across scales. In order to predict the milling time upon scale-up the number of passes, or batch turnover, through the mill was kept constant. However, this prediction of the required milling time was often less successful than the prediction of the terminal particle size. Studies presented here confirmed the importance of maintaining constant rotor tip speed across scales to achieve the predicted terminal particle size and identified the importance of additional parameters to address particle breakage kinetics to allow prediction of the required milling time to achieve the target particle size. Additional aspects of hydrodynamics, shear rates, and equipment properties were assessed as part of these scale-up model optimization efforts. Specific processing parameters evaluated included flow rate, API slurry solids concentration, and starting particle size distribution. Ultimately, the Slot Event Model was developed to incorporate the critical geometric parameters by considering the frequency and the probability of a slot event. In addition to applying the revised model across scales, further model verification was achieved by evaluating custom rotor−stator mill heads. Studies with these custom mill heads provided insight into the importance of mill efficiency and slot events. This, in turn, allowed for more accurate scale-up of not only the terminal particle size but also the milling time required to achieve the target particle size. The success of the optimized model reduces the reliance on in-process controls or at-line testing for determining the end point of milling.

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“…A question arises: Where is the borderline between polymorphism and a sample specific disorder? Recently, multiple articles have been published concerning this issue. ,− The cases of eniluracil and promethazine hydrochloride illustrate how fuzzy the borderline really is. The first is a story of polymorphs later shown to be disordered variations of the same structure.…”

Section: Introductionmentioning

confidence: 99%

Trospium Chloride: Unusual Example of Polymorphism Based on Structure Disorder

Skořepová

Čejka

Hušák

et al. 2013

Crystal Growth & Design

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The characterization of the solid state properties of an active pharmaceutical ingredient is a necessary step in drug development. One such API is trospium chloride, an anticholinergic drug used to treat incontinence and overactive bladder syndrome. One crystal form is known but, from the crystallographic point of view, has only been described by the X-ray powder diffraction pattern. Because, to the best of our knowledge, no crystal structures of trospium chloride have been published, we decided to prepare and describe different crystal forms. Using single-crystal X-ray diffraction, the structures of two new polymorphs and of one unstable solvate were solved. All forms were obtained from ethanol mother liquor. Both polymorphs exhibited a significant pseudosymmetrical disorder. The polymorphs were highly similar but were distinguished by their symmetry and the resulting single-crystal diffraction behavior. A detailed inspection of the molecular packing revealed that variations in the short-range disorder most likely gave rise to these two sibling polymorphs, which are hard to distinguish by X-ray powder diffraction.

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One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability

Cited by 7 publications

References 38 publications

A Practical Review of NMR Lineshapes for Spin-1/2 and Quadrupolar Nuclei in Disordered Materials

A Practical Review of NMR Lineshapes for Spin-1/2 and Quadrupolar Nuclei in Disordered Materials

High-Shear Rotor–Stator Wet Milling for Drug Substances: Expanding Capability with Improved Scalability

Trospium Chloride: Unusual Example of Polymorphism Based on Structure Disorder

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