Theophylline Cocrystals Research Articles

Recent advances in pharmaceutical cocrystals of theophylline.

Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline's additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures.

Supramolecular architecture of theophylline polymorphs, monohydrate and co-crystals with iodine: study from the energetic viewpoint

The supramolecular features in five polymorphs and two co-crystals of theophylline were studied combining experimental and theoretical methods.

Two Polymorphic Cocrystals of Theophylline with Ferulic Acid

In this study, the crystal structures of 1:1 theophylline–ferulic acid cocrystal polymorphs are reported for the first time. Interestingly, both forms crystallize in the same space group but with a different number of molecules in the asymmetric unit (form I = 2; form II = 4). The two polymorphs show distinct crystal morphology, demonstrating prism and rod single crystals, respectively. Theoretical calculations are performed to predict their morphology and thermodynamic stability (form I > form II). The prediction result agrees well with the measured pharmaceutical properties. Form I presents better hygroscopic stability (RH < 95%), slower dissolution, and lower solubility (1.06 ± 0.03, 1.63 ± 0.01, 1.30 ± 0.08 and 4.09 ± 0.05 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions) over form II (8.45 ± 0.33, 2.41 ± 0.17, 3.46 ± 0.26 and 28.71 ± 0.87 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions). In summary, this work elucidates the experimental findings with relevant predictions systematically and enriches our understanding of the structure–property relationship of the theophylline cocrystal system.

To what extent do bond length and angle govern the 13C and 1H NMR response to weak CH⋯O hydrogen bonds? A case study of caffeine and theophylline cocrystals

Weak hydrogen bonds are important structure-directing elements in supramolecular chemistry and biochemistry. We consider here weak CH⋯O hydrogen bonds in a series of cocrystals of theophylline and caffeine and assess to what extent the CH⋯O distance and angle govern the observed 13C and 1H isotropic chemical shifts. Gauge-including projector-augmented wave density functional theory (GIPAW DFT) calculations consistently predict a decrease in the 13C and 1H magnetic shielding constants upon hydrogen bond formation on the order of 2–5 ppm (13C) and 1–2 ppm (1H). These trends are reproduced using the machine-learning approach implemented in ShiftML. Experimental 13C and 1H chemical shifts obtained for powdered samples using one-dimensional NMR spectroscopy as well as heteronuclear correlation (HETCOR) spectroscopy correlate well with the GIPAW DFT results. However, the experimental 13C NMR response only correlates moderately well with the hydrogen bond length and angle, while the experimental 1H chemical shifts only show very weak correlations to these local structural elements. DFT computations on isolated imidazole-formaldehyde models show that the 13C and 1H chemical shifts generally decrease with the C⋯O distance but show no clear dependence on the CH⋯O angle. These results demonstrate that the 13C and 1H response to weak CH⋯O hydrogen bonding is influenced significantly by additional weak contacts within cocrystal heterodimeric units.

Drug-drug cocrystals of theophylline with quercetin

Drug-drug cocrystals have received growing attention in pharmaceutical industry for the ability to present a strategy for the development of fixed-dose combination drugs. In this study, two novel drug-drug cocrystals (one hydrate and one anhydrate) composed of theophylline (THP) and quercetin (QUE) were obtained. The hydrate, THP-QUE-H, was prepared by liquid-assisted grinding method, and the anhydrate, THP-QUE-A, was harvested by heat-treatment of the THP-QUE-H at about 235 °C. Thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis showed that the THP-QUE-H transformed to the THP-QUE-A at about 235 °C and the melting point was 247 °C, indicating both the cocrystals were thermally stable at environment temperature. Additionally, both cocrystals maintained a stable state after 30-day under 25 °C/90% RH condition or after 30-day under 25 °C/15% RH condition. Such results indicate the two THP-QUE cocrystals might show potential as suitable solid forms for the further development as pharmaceutical products.

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline.

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir–theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature–composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

At-line green synthesis monitoring of new pharmaceutical co-crystals lamivudine:theophylline polymorph I and II, quantification of polymorph I among its APIs using FT-IR spectroscopy and MCR-ALS

This paper, reports for the first time the green synthesis of the polymorphs I and II of new pharmaceutical co-crystals lamivudine:theophylline in solid-phase, through the mixture between lamivudine and theophylline (both active pharmaceutical ingredients-APIs) in the proportion of 1:1 by neat grinding and liquid assisted grinding (10 μL ethanol). Fourier transform-infrared (FT-IR) spectroscopy and multivariate curve resolution with alternating least-squares (MCR-ALS) were employed as non-invasive analytical methodology for the at-line green synthesis monitoring of the novels lamivudine:theophylline co-crystals. By MCR-ALS it was possible to identify each component present in a complex matrix, with strong spectral overlapping, containing lamivudine, theophylline, and the novel lamivudine:theophylline co-crystal with high confidence based on the comparison of the pure and recovered spectral and concentration profiles. This model allowed to identify the end of the reaction and understand the mechanism involved in the synthesis through the identification of the intermediates present in the synthesis process. Also, MCR-ALS model estimated the concentration of co-crystal polymorph I with a root mean square error of prediction (RMSEP) and the percentage relative error of prediction (REP%) equal to 3.323 (w/w) and 9.9%, respectively. These were good results since the spectral profile of cocrystal and the physical mixture of its APIs present strong spectral overlapping in their spectral domain. Therefore, the quantification of the co-crystal between its APIs (lamivudine and theophylline) certified that the co-crystal as final product was obtained, collaborating with the results obtained by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD).

Role of Coformer and Excipient Properties on the Solid-State Stability of Theophylline Cocrystals

The stability of theophylline cocrystals composed of acidic (glutaric acid), basic (isonicotinamide), or neutral (benzamide) coformers was evaluated in the presence of several excipients. Tablets of theophylline-glutaric acid (TG) and theophylline-isonicotinamide (TINT) cocrystals were stable “as is” (no excipient) after storage at 40 °C/75% RH for 1 week. However, TG and TINT cocrystals dissociated rapidly in the presence of basic and acidic excipients, respectively. The dissociation reaction was water-mediated, and theophylline, the reaction product, was identified by powder X-ray diffractometry. In the case of theophylline-benzamide cocrystal, storage of tablets with and without excipients at 40 °C/75% RH for 1 week resulted in a cocrystal polymorphic transformation. Thus, the potential for excipient-induced cocrystal dissociation exists for cocrystals composed of acidic and basic coformers. Moreover, if the coformer renders the cocrystal highly water-soluble, even in the presence of neutral excipients...

Tuning mechanical behaviour by controlling the structure of a series of theophylline co-crystals

Six new co-crystals of theophylline with some substituted carboxylic acids, amides and one active pharmaceutical ingredient (API) have been synthesized.

Prediction of Solid State Properties of Cocrystals Using Artificial Neural Network Modeling

Using Artificial Neural Networks (ANNs), four distinct models have been developed for the prediction of solid-state properties of cocrystals: melting point, lattice energy, and crystal density. The models use three input parameters for the pure model compound (MC) and three for the pure coformer. In addition, as an input parameter the model uses the pKa difference between the MC and the coformer, and a 1:1 MC–conformer binding energy as calculated by a force field method. Notably, the models require no data for the actual cocrystals. In total, 61 CCs (two-component molecular cocrystals) were used to construct the models, and melting temperatures and crystal densities were extracted from the literature for four MCs: caffeine, theophylline, nicotinamide, and isonicotinamide. The data set includes 14 caffeine cocrystals, 9 theophylline cocrystals, 9 nicotinamide cocrystals, and 29 isonicotinamide cocrystals. Model-I is trained using known cocrystal melting temperatures, lattice energies, and crystal densitie...

Combining Crystal Structure and Interaction Topology for Interpreting Functional Molecular Solids: A Study of Theophylline Cocrystals

The acoustic frequency distributions, mechanical moduli, and crystal structures for theophylline (THY) and three cocrystals are combined to illustrate how supramolecular organization and interaction topology contribute to the compaction performance of molecular solids. A novel solid form of THY, a cocrystal with 4-fluoro-3-nitrobenzoic acid (FNBA), is reported. This material adopts a 2d-layered structure and has superior tabletability relative to THY. The improved plasticity for THY–FNBA was further corroborated by Heckel analysis with THY–FNBA displaying a reduced yield pressure (Py) relative to theophylline. The performance of THY–FNBA was further compared to a structurally similar theophylline cocrystal with acetaminophen (THY–APAP). Despite structural similarity, their relative compaction performance was distinct. Powder Brillouin light scattering (p-BLS) was used as an experimental measure of the interaction topologies of these materials, and through this approach, the interlayer interaction strength...

Evaluating Suspension Formulations of Theophylline Cocrystals With Artificial Sweeteners

Pharmaceutical cocrystals have garnered significant interest as potential solids to address issues associated with formulation development of drug substances. However, studies concerning the understanding of formulation behavior of cocrystals are still at the nascent stage. We present results of our attempts to evaluate suspension formulations of cocrystals of an antiasthmatic drug, theophylline, with 2 artificial sweeteners. Stability, solubility, drug release, and taste of the suspension formulations were evaluated. Suspension that contained cocrystal with acesulfame showed higher drug release rate, while a cocrystal with saccharin showed a significant reduction in drug release rate. The cocrystal with saccharin was found stable in suspension for over 9 weeks at accelerated test condition; in contrast, the cocrystal with acesulfame was found unstable. Taste analysis using an electronic taste-sensing system revealed improved sweetness of the suspension formulations with cocrystals. Theophylline has a narrow therapeutic index with a short half-life which necessitates frequent dosing. This adversely impacts patient compliance and enhances risk of gastrointestinal and cardiovascular adverse effects. The greater thermodynamic stability, sweetness, and sustained drug release of the suspension formulation of theophylline-saccharin could offer an alternative solution to the short half-life of theophylline and make it a promising formulation for treating asthmatic pediatric and geriatric patients.

A 13C solid-state NMR investigation of four cocrystals of caffeine and theophylline.

We report an analysis of the 13C solid-state NMR chemical shift data in a series of four cocrystals involving two active pharmaceutical ingredient (API) mimics (caffeine and theophylline) and two diacid coformers (malonic acid and glutaric acid). Within this controlled set, we make comparisons of the isotropic chemical shifts and the principal values of the chemical shift tensor. The dispersion at 14.1 T (600 MHz 1H) shows crystallographic splittings in some of the resonances in the magic angle spinning spectra. By comparing the isotropic chemical shifts of individual C atoms across the four cocrystals, we are able to identify pronounced effects on the local electronic structure at some sites. We perform a similar analysis of the principal values of the chemical shift tensors for the anisotropic C atoms (most of the ring C atoms for the API mimics and the carbonyl C atoms of the diacid coformers) and link them to differences in the known crystal structures. We discuss the future prospects for extending this type of study to incorporate the full chemical shift tensor, including its orientation in the crystal frame of reference.

Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co-crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters

The aim of this study was to determine the thermodynamic stability order of co-crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using acetaminophen (AC) co-crystals of oxalic acid (OX), maleic acid (MA), and theophylline (TH). The addition of TH to an AC-MA co-crystal (AC-MA) afforded AC-TH, suggesting that AC-TH was more stable than AC-MA. The stability order among the other co-crystals was determined in the same manner. The stability order of the AC co-crystals was determined to be AC-TH > AC-MA ≈ AC-OX. Interestingly, the addition of TH to AC-OX afforded TH-OX. The stability order of the TH co-crystals was also determined (OX-TH > AC-TH ≈ MA-TH). Although the stability order of the AC co-crystals was consistent with the differences in their hydrogen bond energy (ΔE), an in silico parameter for predicting co-crystal formation, it showed no relationship to the excess enthalpy (Hex). These results suggest that co-crystal formation can be predicted with greater accuracy using ΔE rather than Hex for AC co-crystals. The stability orders of the AC and TH co-crystals also correlated well with their melting points and disintegration temperatures.

Supply and Demand in the Ball Mill: Competitive Cocrystal Reactions

The stability of different theophylline cocrystals under milling conditions was investigated by competitive cocrystal reactions. To determine the most stable cocrystal form under milling conditions, the active pharmaceutical ingredient theophylline was either ground with two similar coformers (benzoic acid, benzamide, or isonicotinamide), or the existing theophylline cocrystals were ground together with a competitive coformer. All competitive reactions were investigated by in situ powder X-ray diffraction disclosing the formation pathway of the milling processes. On the basis of these milling reactions, a stability order (least to most stable) was derived: tp/bs < tp/ba < tp/ina < bs/ina.

X-ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding

Two new cocrystals of theophylline were prepared by liquid assisted grinding. While compound 1 (theophylline:4-aminosalicylic acid 2:1) was characterized by single crystal X-ray diffraction, the crystal structure of compound 2 (theophylline:4-aminobenzoic acid 1:1) was determined by combining X-ray powder diffraction (XRPD), solid-state NMR and DFT calculations. The use of 1D/2D 1H high-resolution solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the building blocks of compound 2, thus providing information on the type of hydrogen bond synthons formed. DFT calculations were also employed to generate meaningful structures and calculate NMR 1H and 13C chemical shifts to further validate the XRPD model. Compound 2 shows an unusual structure, in which the amino groups do not participate in hydrogen bonds, while compound 1 exhibits an extended hydrogen-bonding network, in which planar subunits can be recognized.

Thermodynamics and crystallization of a theophylline–salicylic acid cocrystal

The thermodynamics of the theophylline–salicylic acid cocrystal has been explored and compared with those of another two theophylline cocrystals for an in-depth study of the regular pattern of theophylline cocrystals.

Solid-state NMR studies of theophylline co-crystals with dicarboxylic acids

In this work, three polycrystalline materials containing co-crystals of theophylline with malonic, maleic, and glutaric acids were studied using 13C, 15N and 1H solid-state NMR and FT-IR spectroscopy. The NMR assignments were supported by gauge including projector augmented waves (GIPAW) calculations of chemical shielding, performed using X-ray determined geometry. The experimental 13C cross polarization/magic angle spinning (CP/MAS) NMR results and the calculated isotropic chemical shifts were in excellent agreement. A rapid and convenient method for theophylline co-crystals crystal structure analysis has been proposed for co-crystals, which are potentially new APIs.

Hydrogen bond synthon competition in the stabilization of theophylline cocrystals

In the preparation of theophylline cocrystals, phenol coformers facilitate water assimilation due to their weaker O–H⋯N(imidazole) synthon. The presence of –COOH prevents water incorporation and provides added physical stability at high humidity. This study shows the feasibility of cocrystal design of an API to tune physical properties based on hydrogen bond synthons.

Tuning physicochemical properties of theophylline by cocrystallization using the supercritical fluid enhanced atomization technique

Formation of different micro- to nanosized cocrystals of theophylline is addressed by using the supercritical enhanced atomization (SEA) process. The experimental results presented here help to highlight how to prepare cocrystals of theophylline (TPL) using a supercritical fluid-based technique to accomplish the required physicochemical properties of that active pharmaceutical ingredient (API). The SEA process shows a strong versatility and feasibility towards the formation of highly pure theophylline cocrystals, using tetrahydrofuran as a solvent. The formation of TPL cocrystals with different types of morphology and dissolution behaviour/properties is induced by using different coformers, such as urea, saccharin, gentisic acid, salicylic acid, glutaric acid, sorbic acid, 1-hydroxy-2-naphthoic acid, oxalic acid, maleic acid and nicotinamide. The solubility of each coformer in the dissolution medium of phosphate-buffered saline (pH 7.4 at 25°C) could determine the dissolving rate behaviour of the produced cocrystals. Consequently, the low-soluble coformers generate TPL cocrystals with a slow-dissolving rate, while the use of highly soluble coformers produces faster-dissolving TPL cocrystals. Albeit the SEA process operating temperature influences the mean cocrystal particle size, this technique shows a high potential as an effective cocrystal screening tool.