New and Noteworthy Scientific Publications From Our Scientists:
Whitepapers & Technical Notes
White Paper
Q4 2024
Microcrystal Electron Diffraction Study of Multi-component Salt and Cocrystal Forms of 3-Nitrobenzoic Acid and Pyrimethanil
Stephan X.M. Boerrigter and G. Patrick Stahly, Triclinic Labs, Lafayette IN, USAThis comprehensive study delves into how Microcrystal Electron Diffraction (MicroED) complements traditional X-ray diffraction (XRD) methods, especially when working with challenging multi-component systems. Three single-phase crystals containing 3-nitrobenzoic acid (NBA) and pyrimethanil (PYR) in a 1:1 stoichiometry were found, and their structures were determined. This system (NBA•PYR), whose components have a ΔpKa < 1, can crystallize in one salt and two cocrystal forms. Structures were determined using both single-crystal X-ray diffraction (XRD) and microcrystal electron diffraction (microED). Both methods produced essentially equivalent crystallographic results that independently allow the solid form assignment of either salt or cocrystal. A remarkable result from the microED analysis was the complete crystal structure solution of a new polymorph of the cocrystal from a single impurity particle.
Application Note
Q4 2023
A Comprehensive Approach for Solid Form Selection in Preclinical Development and Beyond.
Melanie Bevill, Chris Seadeek, Nico Setiawan, Shawn Comella, Blaise Mibeck, Steef BoerrigterDifferent solid forms (polymorphs, salts, cocrystals) of an active pharmaceutical ingredient (API) can have very different physico-chemical properties. Those differences can impact bioavailability, solubility, dissolution rate, side effect incidence, stability, API and drug product manufacturability, and other important parameters. Most APIs can exist in multiple solid forms, including polymorphs, hydrates, solvates, salts, cocrystals, and non-crystalline forms. The goal in screening and selection is to produce an optimal solid form based on parameters such as crystallinity, stability, solubility, hygroscopicity, and ease of production ("manufacturability"). Understanding the process chemistry is paramount for reproducibility during drug development and manufacturing. Here we discuss various solid forms and a comprehensive way to approach solid form screening for regulatory, manufacturing, financial, and intellectual property needs.
Keywords: Polymorphism, pharmaceutical salt, pharmaceutical cocrystal, amorphous materials, solid-state intellectual property.
Application Note
Q4 2023
Rapid Development of an Amorphous Solid Dispersion (ASD) – Nifedipine (NIF)
Nico SetiawanAmorphous solid dispersions (ASD) have long been used to increase the solubility and bioa-vailability of poorly-soluble compounds. A considerable amount of research has been carried out and has generated useful techniques in the area of ASD development. Surprisingly, the number of examples with successful application of the available techniques has been meager. Herein, a case study with nifedipine is presented where ASD candidates were rapidly determined within 2-3 weeks by utilizing a compilation of these techniques. Keywords: Amorphous Solid Dispersion (ASD), Spray Drying, Crystallization, Solubility, Stability, Dissolution.
Keywords: Polymorphism, pharmaceutical salt, pharmaceutical cocrystal, amorphous materials, solid-state intellectual property.
Application Note
Q2 2023
Utility of Low Frequency (LF) Raman Mapping: Dissolution of Acetaminophen (ACE) Spray Dried Dispersions (SDD)
Nico Setiawan, Ph.D., Andrew Smith, and David E. Bugay, Ph.D.This application note outlines the evaluation of post-dissolution ACE SDD. The results indicated that in all of the cases studied, ACE remained amorphous upon dissolution if it was intimately mixed in the dispersion. However, phase separation from the polymer allowed ACE to crystallize as expected. Interestingly, the type of polymer used affected the ACE polymorph generated. The mixture of polymorphs was observed in the powder X-ray diffraction (PXRD) result (though it could easily be overlooked), while LF Raman maps showed distinct regions of the different polymorphs. This study demonstrated the utility of LF Raman mapping in elucidating the dissolution mechanism of amorphous dispersions. Keywords: Low Frequency Raman, Amorphous, Spray dried dispersion, Dissolution, Crystallization, Polymorphs
Application Note
Q2 2023
Identification of Cellulosic Fibers by Infrared Spectroscopy and Scanning Electron Microscopy
Sidnie BienzThis application note demonstrates how scanning electron microcopy (SEM) can be used in conjunction with Infrared (IR) micro spectroscopy to identify different cellulosic fibers based on surface features and overall fiber appearance.
White Paper
Q2 2019
Application of Low-Frequency (LF) Raman Spectroscopy to an Isoenergetic Polymorph Study
G. Patrick Stahly, Ph.D.The importance of polymorphism in the pharmaceutical industry is well established. Much literature exists describing the effect of polymorphs on efficacy, the phenomenon of polymorphism, and the analytical tools available to study polymorphism in active pharmaceutical ingredients and drug products. Standard analytical techniques in the study of polymorphism include x-ray diffraction, differential scanning calorimetry, thermogravimetry, vapor sorption analysis, vibrational spectroscopy, and solid-state nuclear magnetic resonance spectroscopy. Here we discuss the use of low frequency (THz) Raman spectroscopy for differentiation of solid forms.
Technical Note
Q1 2019
Novel Non-Crystalline Materials Analysis: New Strategies to De-risk Amorphous Material Formulation Development.
Simon Bates, Ph.D.The latest approaches for characterizing non-crystalline (amorphous) materials and determining physical stability under typical storage conditions. Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice. Different forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Instability of non-crystalline materials is of particular concern to regulatory bodies within companies and national agencies.
White Paper
Q4 2017
Cocrystals: A Regulatory Rebirth
G. Patrick Stahly, Ph.D.What is the impact of recent changes in FDA guidance on regulatory and intellectual property issues?
The FDA reclassification of cocrystals as active pharmaceutical ingredients (APIs) has created exciting opportunities for the pharmaceutical industry. That reclassification means cocrystals can now be developed as if they were polymorphs, providing new avenues for dealing with poor API physical properties and extending intellectual property lifetimes. It is important to understand how the revised guideline impacts API development, regulatory submissions, and intellectual property protection. Those topics are discussed in this whitepaper. Also considered is the importance of identifying whether an API is a salt or a cocrystal, a critical classification from a regulatory point of view. In addition, a list of FDA-approved, marketed cocrystals is presented. Finally, recommendations for cocrystal screening, evaluation, formulation, and production at scale are given.
White Paper
Q4 2018
Application of Chemometrics in Solid- State Development
Simon Bates, Ph.D.The Triclinic Labs Chemometric Engine is built around randomly generated conditional inference trees (decision trees) [Breiman 2001 and Hothorn et al 2006]].
This allows for an unbiased classification of the similarities and differences between a set of input data files that is not tied to the analytical tools used to collect the data and is not dependent on the type of material being studied.
For each tree, the observations used to define the classification of a data file at each decision node are randomly selected from the input data set, which allows the method to identify the most predictive observations from out of the input data set (learning algorithm). The random nature of the individual tree growing and subsequent assembly of individual trees into multiple classification forests further allows for an inbuilt error estimate for the classification results which is generated as part of the classification process
Publications:
Sucrose Lyophiles: A Semi-Quantitative study of residual water content by Total X-Ray Diffraction Analysis
European Journal of Pharmaceutics and Biopharmaceutics. June 2013
Nail, S. (Baxter Pharmaceutical Solutions), Bates, S., Jonaitis, D.(Triclinic Labs)The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State
Childs, S. L.;
Stahly, G. P.;
Park, A.
Molecular Pharmaceutics 2007, 4, 323-338
Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals
Crystal Growth & Design 2007, 7, 1007-1026
Stahly, G.P.A detailed description of polymorph screening procedures is presented. On the basis of the results of 245 polymorph screens, organic compounds were found to exist in multiple solid forms quite frequently. About 90% exhibited multiple crystalline and noncrystalline forms; about 50% exhibited polymorphism. Cocrystals are defined, and cocrystal screening is discussed. Data from 64 cocrystal screens show that cocrystals were found in 61% of the cases, and the total number of cocrystals found was 192.
Crystal Engineering Approach To Forming Cocrystals of Amine Hydrochlorides with Organic Acids. Molecular Complexes of Fluoxetine Hydrochloride with Benzoic, Succinic, and Fumaric Acids
JACS 2004, 126(41), 13335-42
Childs, et. al.A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors.
The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride.
On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water.
Chemical Identity Testing by Remote-Based Dispersive Raman Spectroscopy
Appl. Spectrosc. 64(5),467-475 (2010)
D.E. Bugay and R.C. BrushThe advent of robust, rugged, and current Good Manufacturing Practices (cGMP) compliant hand-held Raman spectrometers provides a wealth of opportunities for the analytical pharmaceutical chemist to bring the laboratory to the sample. This paper discusses the use of hand-held Raman spectrometers for the development of qualitative chemical identification methods for a number of well-known pharmaceutical products (tablets and capsules). Methods were developed on two different instruments and transferred to a third instrument for application of the methodology to independently obtained drug products.
A novel decision algorithm is presented for the assessment of the correlation between the Raman spectrum of the unknown sample to the spectrum of the authentic reference material. This novel algorithm considers accuracy but more importantly precision (uncertainty/reliability), thus removing human bias that is associated with typical spectral searching approaches. The results presented in this paper show the reliability of developing, validating, and transferring chemical identification assays on hand-held Raman spectrometers.
Estimation of the Glass Transition Temperature (Tg) of an Amorphous Drug Substance from Dispersions in Polymeric Carriers (2011 Poster)
Victor C. Rucker and Jodi Fausnaugh-Pollitt, Gilead Sciences, Foster City, CA Michael DeLion and G. Patrick Stahly, Triclinic Labs, Inc. , West Lafayette, INA poorly soluble BCS Class IV drug is proposed for dosing from
the amorphous state. Determining the Tg of the drug is essential for assessing the physical stability of the amorphous form. It was necessary to determine the Tg of a x-ray amorphous drug to be delivered in the amorphous form. Polarized Light Microscopy analysis indicated the material was ordered, suggesting a mesophasic material. The Tg was estimated from mixtures of the test article with polymers of a known Tg. It was estimated that the Tg is > 50 °C above any expected storage temperature that would be encountered by the amorphous drug.
Assessment of the nature of disorder and its effect on recrystallization tendency in a hydrate-anhydrate system
(AAPS 2011 Poster)
Paroma Chakravarty, Joseph Lubach, Small Molecule Pharmaceutical Sciences, Genentech, Inc. , and Simon Bates Triclinic Labs, Inc.Two crystallization endotherms were observed in dehydrated
and ball milled samples (= 20 min milling). An Increase in milling time leads to greater local order. The highest degree of local order is observed in ball milled (60 min, HF) and dehydrated samples. Since the nature of local order influences propensity of crystallization and the resulting crystalline phase, the delayed onset of crystallization in these samples with greater local order suggests presence of a lattice order unlike that in the known crystalline phases.
VIDEO
Detecting Adulterated Drugs
Dr. David Bugay, Triclinic Labs, IncWatch the Youtube Video as Dr. Bugay discusses new technologies to detect pharmaceutical adulteration at the US Pharmacopeia Annual Meeting in 2009
Video Link
Read a recent public court ruling on a case in which Triclinic scientists were involved as experts
CEPHALON, INC., and CIMA LABS, INC. Plaintiffs, v. WATSON PHARMACEUTICALS, INC., WATSON LABORATORIES, INC.,and WATSON PHARMA, INC.
"Cephalon has demonstrated, by a preponderance of the evidence, that Watson infringes claims 3, 5, 32 and 54 of the '981 patent. Watson has not met its burden to prove invalidity of the asserted claims by clear and convincing evidence."
