Sathyanarayana Reddy Perumalla

Ionized form of acetaminophen with improved compaction properties

The most widely used antipyretic and analgesic drug, acetaminophen, has the long standing problem of extremely poor tableting properties and has been considered as non-ionizable. Here we report the synthesis of the first ionized solid-state structure, acetaminophen HCl monohydrate, and demonstrate its excellent tableting properties.

Improved solid-state stability of salts by cocrystallization between conjugate acid–base pairs

The cocrystallization between a carboxylic acid and its conjugate base forms materials exhibiting improved physical and chemical stability over corresponding regular salts.

Enabling Tablet Product Development of 5-Fluorocytosine Through Integrated Crystal and Particle Engineering

The antifungal drug, 5-fluorocytosine (FC), is marketed as a capsule (250 or 500 mg strength) instead of the preferred tablet dosage form. Through systematic characterization of solid-state properties, including mechanical properties, we identify tabletability and poor physical stability of FC as the problems that likely have prevented the successful development of a FC tablet product. We then design an FC oxalate 2:1 salt (FCOXA21), based on established relationship between crystal structure and properties, to address these deficient properties. FCOXA21 is subsequently used to develop a direct compression tablet product using predictive and material-sparing powder characterization tools, that is, ring shear cell for powder flowability and compaction simulator for powder tabletability. The initial tablet formulation, which contains 84.5% (wt %) FCOXA21, exhibits excellent tabletability but inadequate flowability. We solve the powder flowability problem through controlling the particle size of FCOXA21. A batch of FCOXA21 tablets (500 mg FC equivalent dose) is then prepared. Finally, systematic evaluation on tablet weight variation, content uniformity, friability, and dissolution using standard methods confirms the commercial manufacturability of FC tablets. Through this work, we have demonstrated the potential of integrated crystal and particle engineering in expediting the development of tablet products of challenging drugs using the economical direct compression process.

Design, synthesis, and characterization of new 5-fluorocytosine salts.

5-Fluorocytosine (FC), an antifungal drug and a cytosine derivative, has a complex solid-state landscape that challenges its development into a drug product. A total of eight new FC salts, both cytosinium and hemicytosinium, with four strong acids were prepared by controlling acid concentration in the crystallization medium. The pharmaceutically acceptable saccharin salt of FC exhibits superior phase stability and, hence, has the potential to address the instability problem of FC associated with hydration.

Dependence of tablet brittleness on tensile strength and porosity

An analysis of data collected from 25 sets of diverse pharmaceutical powders has identified that an exponential growth function satisfactorily describes the relationship between tablet brittleness and tablet porosity while a power law function well describes the relationship between tablet brittleness and tensile strength. These equations have the potential to facilitate better characterization of tablet mechanical properties and to guide the design and optimization of pharmaceutical tablet products.

Confused HCl: Hydrogen Chloride or Hydrochloric Acid?

Hydrogen chloride (HCl) is a gas under standard conditions. HCl has been commonly used, either in the gaseous form or as solutions, for many applications, such as synthesis of both organic and inorganic compounds, salt formation, pH control and neutralizations, and surface cleaning. Hydrochloric acid is an aqueous solution of HCl (pKa = 6), with the formula of HCl ACHTUNGTRENNUNG(H2O)x (x decreases with increasing concentration of HCl). Despite the fundamental differences in both chemical compositions and physical states between them, the abbreviation “HCl” is commonly misused to represent hydrochloric acid while HCl solutions in other solvents have been rarely discussed. This misuse is found in chemistry textbooks. The confusion in the terminology also persists well into the current literature, including peerreviewed journals and common reference sources. Herein, we highlight the need of clarifying the confusion by showing the distinct behaviors of other forms of HCl and HCl ACHTUNGTRENNUNG(H2O)x in solid-state protonation of several common compounds. In recent years, the design, synthesis, and prediction of new solid-state structures have gained enormous interest because of fundamental, practical, and legal interests. Efforts by researchers around the world, under the umbrellas of crystal engineering, supramolecular chemistry, and solidstate chemistry, have led to significant progress in the synthesis of novel functional materials and successful crystal structure predictions. Hydrochloride salts are used in various branches of science ranging from chemical synthesis, to separation, and to pharmaceuticals. For example, it is estimated that over half of the medicines on the market are administered as salts, out of which, more than half of the salts of basic drugs are hydrochlorides. Perhaps because of both the wide availability of HClACHTUNGTRENNUNG(H2O)x in common laboratories and the confusion in the terminology, synthesis of hydrochloride salts is usually attempted using HCl ACHTUNGTRENNUNG(H2O)x instead of other forms of HCl. This practice generally leads to difficulty in the formation of hydrochloride salts of poorly ionizable bases. For example, solid-state protonation of carboxamide (or amide), weakly basic N-heterocycles functional groups, have been declared to be extremely difficult, if not impossible. Moreover, an estimated 30 % of APIs are considered non-ionizable in the solid state, for which salt formation has been generally excluded as a possible approach for solving drug delivery problems. However, since HCl can form a superacid when dissolved in suitable solvents, we hypothesize that solid-state protonation (or salt formation) of even poorly ionizable bases is possible by using HCl organic solutions other than HCl ACHTUNGTRENNUNG(H2O)x. An added advantage of using HCl organic solutions is the ability to prepare anhydrous HCl salts and the possibility of screening for their polymorphs. Carbamazepine (CBZ, Scheme 1) is a urea derivative drug for treating epilepsy and trigeminal neuralgia. Because of its importance in health care, extensive research

Synthon preference in O-protonated amide crystals – dominance of short strong hydrogen bonds

Although the amide functional group is weakly ionizable, there have been serendipitous discoveries of amide salts. To facilitate their systematic design, we sought to identify the preference of 12 possible synthons in oxygen protonated amide structures. An analysis of a total of 81 protonated amide crystal structures retrieved from the Cambridge Structural Database and 12 new protonated amide structures prepared by us, revealed that ∼86% of these structures involving charge assisted short strong hydrogen bonds, including ∼54% of the hydrogen bridged dimers formed between protonated and neutral amide. The probability of forming hydrogen bridged dimers increases in the order of primary amide < secondary amide < tertiary amide. The two previously missing synthons, R22(8) and R12(6), in primary amides are realized for the first time in this work. However, the two predicted ring (R) hydrogen bonding synthons, R22(8) and R12(6), for cis secondary amides remain to be discovered.

Enabling the Tablet Product Development of 5-Fluorocytosine by Conjugate Acid Base Cocrystals

5-Fluorocytosine (FC) is a high-dose antifungal drug that challenges the development of a tablet product due to poor solid-state stability and tabletability. Using 2 pharmaceutically acceptable conjugate acid base (CAB) cocrystals of FC with HCl and acesulfame, we have developed commercially viable high loading FC tablets. The tablets were prepared by direct compression using nano-coated microcrystalline cellulose Avicel PH105 as a tablet binder, which provided both excellent tabletability and good flowability. Commercial manufacturability of formulations based on both CAB cocrystals was verified on a compaction simulator. The results from an expedited friability study were used to set the compaction force, which yielded tablets with sufficient mechanical strength and rapid tablet disintegration. This work demonstrates the potential value of CAB cocrystals in drug product development.

Solid-state characterization of optically pure (+)Dihydromyricetin extracted from Ampelopsis grossedentata leaves

Dihydromyricetin (DMY) is a natural flavanol compound isolated from a traditional Chinese medicine, Ampelopsis grossedentata. Despite that optically pure (+)DMY is desired for treating chronic pharyngitis and alcohol use disorders, only DMY racemate is commercially available due to prolonged exposure time to high temperature and the presence of metal ions during industrial extraction, which cause racemization of the homochiral (+)DMY. We have developed an extraction method for successfully obtain optically pure (+)DMY. We have further assessed the physicochemical properties of the two phases using PXRD, DSC, TGA, FTIR, and moisture sorption. Among them, PXRD and FT-IR are suitable for quickly distinguishing homochiral (+)DMY from racemic (±)DMY. Lastly, with the aid of cocrystallization with theophylline, the absolute configuration of homochiral (+)DMY was identified to be (2R, 3R).

Robust bulk preparation and characterization of sulfamethazine and saccharine salt and cocrystal polymorphs

The complex between sulfamethazine and saccharine (SMT–SAC) can exist in two polymorphs, one is a cocrystal and the other is a salt. It is important to fully characterize the two polymorphs for a better understanding of the rare polymorphism between a salt and a cocrystal. However, this effort was hindered by the difficulty in reproducibly preparing a large quantity of phase pure cocrystal polymorph (form II). Here, we developed a method for preparing phase pure cocrystal polymorph robustly by controlling the crystallization medium. Using bulk powders, we determined their free energy diagram, by using intrinsic dissolution rates at 5–37 °C and thermal data near melting temperature. We have shown that the two forms are monotropically related, with the cocrystal form II being more thermodynamically stable up to the melting temperature. We further probed their ionization states based on analyses of the position of protons, bond length, and molecular vibrational motions of pertinent functional groups. Finally, the cocrystal form II exhibited notable differences in moisture sorption and compaction properties, which may influence the choice of solid forms for further development of tablet products.