Orn Almarsson

Drugs as materials: valuing physical form in drug discovery

Traditionally, potency and selectivity (and to some extent metabolism) have been the key parameters to consider in the process of discovering new drug candidates. Recently, heads of research and CEOs have been learning a new reality: drugs can move around the body and act at the molecular level, but the chemical and material properties of their physical form need to be identified and optimized for in vivo performance, reliable manufacture and the protection of intellectual property. This review discusses the challenge of pharmaceutical materials discovery, and suggests strategies for addressing the characterization and evaluation of physico-chemical and material properties in the drug discovery and development process.

Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization

Pharmaceutical compounds are molecular solids that frequently exhibit polymorphism of crystal form. One high profile case of polymorphism was ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in 1996. In 1998, a lower energy, more stable polymorph (form II) appeared, causing slowed dissolution of the marketed dosage form and compromising the oral bioavailability of the drug. This event forced the removal of the oral capsule formulation from the market. We have carried out high-throughput crystallization experiments to comprehensively explore ritonavir form diversity. A total of five forms were found: both known forms and three previously unknown forms. The novel forms include a metastable polymorph, a hydrate phase, and a formamide solvate. The solvate was converted to form I via the hydrate phase by using a simple washing procedure, providing an unusual route to prepare the form I “disappearing polymorph” [Dunitz, J. D. & Bernstein, J. (1995) Acc. Chem. Res. 28, 193–200]. Crystals of form I prepared by using this method retained the small needle morphology of the solvate and thus offer a potential strategy for particle size and morphology control.

Application of high throughput technologies to drug substance and drug product development

Abstract This presentation describes the application of novel high throughput physical–chemical technologies to the pharmaceutical discovery and development process. The rationale for such platforms is described in light of the changes that have occurred in the biological and chemical processes leading to drug target evaluation and lead identification. Several high throughput platforms are described for identification and evaluation of solid forms and formulations of drug candidates including salt, hydrate and solvate selection and polymorph discovery and evaluation. The application to the development of oral and intravenous formulations for animal model and human clinical evaluation is also discussed. The importance of informatics to design experiments and capture and analyze data is highlighted. Examples are described showing the power of high throughput systems to discover knowledge that enables pharmaceutical scientists to make more informed and better decisions about product development choices.

The A to Z of pharmaceutical cocrystals: a decade of fast-moving new science and patents.

From aspirin to zoledronic acid, pharmaceutical cocrystals emerged in the past decade as a promising new weapon in the arsenal of drug development. Resurgence of interest in multicomponent crystal compositions has led to significant advances in the science of cocrystal design and discovery. These advances have built upon crystal engineering, which provides a deep understanding of supramolecular interactions between molecules that govern crystal packing and physicochemical properties of crystalline materials. Concomitantly, the patent landscape of pharmaceutical cocrystals developed rapidly in the last decade. This review presents a broad survey of patents issued in the area of pharmaceutical cocrystals. In addition, the review contains analyses of key patents in the area involving compositions and methodologies. Along the way, the main events of the past decade representing a renaissance of cocrystals of pharmaceutical materials are chronicled. Future directions in the area are discussed in light of key pending patent applications and recent publications of seminal interest.

Studies on a hydrocarbon capped free base tetraphenylporphyrin and its conjugate acids - first observation of a monoprotonated tetrapehylporphyrin &{;CapTPP(H3+)CF3CO2−&};

Abstract 1 H-NMR and visible absorbtion spectroscopic titrations of a unique hydrocarbon capped porphyrin 3 H 2 with trifluoroacetic acid in chloroform result in the formation of a monoprotonated porphyrin species 3 H 3 + &{;CF 3 CO 2 − &};. This represents the first observation of a monobasic tetraphenylporphyrin acid. The monocation forms the dibasic 3 H 4 2+ &{;CF 3 CO 2 −&};2 upon further addition of acid. Back-titration of 3 H 4 2+ &{;CF 3 CO 2 − &}; 2 with DMSO demonstrates that the monocation can be generated from the diacid as well as the free base porphyrin. The capping structure on one face of the tetraphenylporphyrin is suggested to diminish the extent of solvation of one proton of 3 H 4 2+ &{;CF 3 CO 2 − &};, thereby rendering the first dissocation constant (represented by C 50(1) ) considerably larger than the second dissociation (C 50(2) ). 19 F NMR chemical shifts of the counterions of −50°C show a similarity to the CF 3 CO 2 − counterions of TPP H 4 2+ &{;CF 3 CO 2 − &}; 2 and indicated a strong association with the prophyrin acid species. 2D NMR ROESY spectroscopy with Distance Geometry Refinement afforded a solution structure for 3 H 2 , from which representative structures of possible inclusion compounds 3 H 3 + &{;CF 3 CO 2 − &}; and 3 H 2 &{;CHCl 3 &}; were created by molecular modeling. Although the dome of the capping structure is predicted to be large enough to accommodate a trifluoroacetate anion on the inside, 19 F NMR spectra and FAB-mass spectra do not support the presence of an acid-base inclusion compound.

A high-throughput approach towards a novel formulation of fenofibrate in omega-3 oil

A novel lipid formulation containing fenofibrate in omega-3 oil was developed using a novel high-throughput screening platform. The optimized formulation combines the cardiovascular health benefits from omega-3 oil with the potent lipid-regulating effect of fenofibrate. When tested against the current marketed product Tricor in healthy human volunteers, the new formulation was shown to be equivalent to Tricor.

A Novel, Lipid-Free Nanodispersion Formulation of Propofol and Its Characterization

No HeadingPurpose.Propofol is a widely used anesthetic agent with highly desirable fast “on” and “off” effects. It is currently formulated as lipid emulsions, which are known to support microbial growth. In this study, a novel, lipid-free nanodispersion formulation of propofol was characterized.Methods.The formulation was evaluated for its physical and chemical stability, in vitro compatibility with red blood cells, and its antimicrobial effectiveness. In vivo pharmacokinetic and pharmacodynamic properties of the formulation were evaluated in rats.Results.Our data suggest that this lipid-free formulation is physically and chemically stable. Compared to the commercial emulsion formulation Diprivan, it causes less hemolysis with red blood cells and has improved antimicrobial activity. In addition, the lipid-free formulation demonstrates similar pharmacological effects to Diprivan in rats.Conclusions.This novel, lipid-free formulation exhibits improved in vitro properties without compromising in vivo effects, therefore representing a promising new alternative for propofol.

The synthesis of a porphyrin with a hydrocarbon encapsulated face

Abstract The uniquely hydrocarbon-like capped porphyrin (C70H68N4), 1i, has been successfully prepared by a high dilution reaction of pyrrole with tetrakis-1,2,4,5-[pentyl-5′-(2″-formylphenyl)]-benzene 1h in the presence of boron trifluoride etherate. The aldehyde 1h was prepared by four simultaneous Wittig condensations of a phosphonium salt, 1e, with 1,2,4,5-tetraformylbenzene, followed by reduction of the double bonds with Raney nickel and deprotection with perchloric acid.

Celecoxib sodium salt: engineering crystal forms for performance

Crystalline hydrates and propylene glycol solvates of celecoxib sodium salt (Cel-Na) were prepared and characterized with the aim of improving oral drug absorption by breaking up the H-bonding interactions present in crystals of the poorly soluble marketed form of the drug (Cel-III). The hydrate grows rapidly from aqueous alkaline solution, forming a thick slurry of thin plates. Thicker plates for structure determination were successfully grown by adding up to 1% benzyl alcohol to the solution. The structure of the pentahydrate of the sodium salt is comprised of a bilayer motif where three waters are coordinated to sodium ions in a discrete layer, while the other two waters reside in a one-dimensional channel. At a given temperature, the hydration state changes rapidly and reversibly as a function of relative humidity (RH). The hydrated salt is physically stable in a sealed vial, but reverts rapidly to the crystalline free base if exposed to ambient CO2 in air at 40% RH or higher. The propylene glycol (PG) solvate of Cel-Na exists in an anhydrous and trihydrate form. The trihydrated PG solvate of Cel-Na is physically stable above ∼15% RH and does not react measurably with CO2 at 66% RH over 4 days, making it the most suitable form for use in solid pharmaceutical formulations.