Lidocaine Pharmaceutical Multicomponent Forms: A Story about the Role of Chloride Ions on Their Stability

10 Feb.,2023

 

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In this work, we focus on comparing the ability ofandto cocrystallise with hydroquinone, resorcinol, and pyrogallol, to form multicomponent pharmaceutical solids, and we study how structure can affect physicochemical properties and usability compared to the parent API. The reported multicomponent solids ofandwere cocrystallised through liquid-assisted grinding (LAG), a versatile and green synthetic method for obtaining solid forms [ 10 11 ] that uses mechanical forces to induce chemical transformations, which is a fast and appropriate tool for multicomponent form screening. The resulting multicomponent forms were characterised by powder X-ray diffraction (PXRD), X-ray differential scanning calorimetry/thermogravimetric analysis (DSC/TGA), Fourier-transform infrared spectroscopy (FTIR), and single-crystal X-ray diffraction (SCXRD). In addition, a thorough analysis of the structural details of the corresponding solids forms obtained forandwas carried out to unravel the influence of the structure on some relevant physicochemical properties, i.e., solubility and stability.

Polyhydroxy benzenes ( Figure 1 ) are a group of compounds intensely studied and utilised as coformers with multiple APIs including lidocaine [ 7 ]. Indeed, they are included in the Generally Recognised as Safe (GRAS) or Substances Added to Food (EAFUS) lists of the US Food and Drug Administration (FDA). Interestingly, these compounds are quite good H-donors; thus, they can easily form hydrogen bonds with other H-acceptor groups such as amide groups, making them excellent candidates to act as coformers in lidocaine formulations, as already reported for phloroglucinol [ 7 ], allowing a comparative study of the structural effect of chlorine in the final products [ 7 ].

shows low solubility in the base form [ 5 ]. Therefore, in pharmaceutical formulations, lidocaine is generally used as its hydrochloride derivative. Solubility problems are certainly a big concern regarding the efficacy of oral administration drugs. Hence, ifwants to be directly included in drug formulations, one of the best approaches seems to be the development of novel multicomponent pharmaceutical solids, a well-established method able to modulate the physicochemical and biopharmaceutical properties of APIs [ 6 ], such as stability, solubility, or manufacturability. In this context, only a few studies can be found in the literature reporting a lidocaine base [ 7 9 ], wheresalts with improved properties were obtained. To build such multicomponent solids, the lidocaine molecule offers different functional groups able to participate in supramolecular synthons ( Figure 1 ), e.g., an amide group that allows hydrogen bonding and an aromatic moiety that can interact through π interactions. These groups are good candidates for interaction with other aromatic rings and alcohol groups, among others.

Lidocaine (2-diethylamino--(2,6-dimethylphenyl)acetamide), hereafter, is an active pharmaceutical ingredient widely used as an anaesthetic in intravenous injection to treat and prevent pain [ 1 2 ] in some medical procedures. It is also used in clinics as an antiarrhythmic drug [ 3 ] to treat ventricular arrhythmias, specifically ventricular tachycardia and ventricular fibrillation, or as a vasoconstrictor in topical applications [ 4 ].

In the past years, crystal engineering and, more particularly, cocrystal design has raised the attention of the pharmaceutical industry as an efficient method to develop new pharmaceutical solid forms. The main advantages of such pharmaceutical cocrystals include not only the enhancement of the physicochemical properties of active pharmaceutical ingredients (APIs) but also the potential of obtaining synergic effects in codrug formulations, keeping the options for intellectual property rights open at lower costs.

2. Materials and Methods

All compounds were commercially available from Sigma-Aldrich (St. Louis, MO, USA) and used as received. Solvents were of HPLC grade and were also supplied from Sigma-Aldrich.

2.1. Liquid-Assisted Grinding (LAG)

12,(lid) and (lidhc) with the coformers resorcinol (res), hydroquinone (hq), and pyrogallol (pyr) were gently ground for 30 min at 25 Hz in a Retsch MM400 ball mill (Haan, Germany). A multiple milling homemade accessory allowing for grinding 12 samples at once was used, placing 12 2 mL Eppendorf tubes with three corundum 1 mm balls each.

For the LAG [ 10 13 ] experiments, different molar ratios of about 100 mg scale and 100 µL of dichloromethane (DCM) were added to each tube. Stoichiometric mixtures of lidocaineandwith the coformers resorcinol, hydroquinone, and pyrogallolwere gently ground for 30 min at 25 Hz in a Retsch MM400 ball mill (Haan, Germany). A multiple milling homemade accessory allowing for grinding 12 samples at once was used, placing 12 2 mL Eppendorf tubes with three corundum 1 mm balls each.

Three different stoichiometries (1:1, 2:1, 1:2) were screened for each system. The powder materials obtained were analysed by PXRD, FTIR, and DSC/TGA to determine the formation of cocrystals. Cocrystals exhibited distinct PXRD patterns and melting points compared to the starting materials.

2.2. Stability Experiments

In order to investigate the stability with respect to dissociation, a suspension of about 100 mg scale was made with 0.5–1 mL of 0.9% NaCl solution. The suspensions were subjected to magnetic stirring at ambient conditions for 24 h without drying completely, keeping a slurry all the time. Aliquots of the slurry were taken, gently ground, and analysed by PXRD to determine if the cocrystal was dissociated into its components, suffered any transformation, or remained stable in the cocrystal form.

To study the influence of temperature and humidity on the stability of the new phases, these materials were left in a temperature/humidity-controlled chamber with a temperature of 40 °C and 75% relative humidity for 2 months, taking sample aliquots during this time to be analysed by PXRD to evaluate the stability of the crystalline phase. All the samples remained stable as a cocrystal form after 2 months.

2.3. Hetero-Seeding Experiments

In order to obtain single crystals suitable for SCXRD characterisation, evaporation experiments were performed from saturated solutions of the different powders obtained from LAG experiments in DCM. In almost all six cases, single crystals suitable for SCXRD were obtained, except for the (lid)2(res) phase, which only formed a microcrystalline material. A hetero-seeding approach was used to obtain single crystals for this phase, using microcrystalline phases obtained for other coformers with predictably similar structures, getting good results using (lid)2(hq) as the hetero-seed. This was confirmed after the structure solution because both new cocrystals were isostructural.

For the seeding experiment, a few micrometric solid particles of hetero-seed powder (lid)2(hq) were added to the liquified mixture obtained from (lid)2(res) LAG experiments, which immediately started to crystallise as single crystals later identified as (lid)2(res).

For the remaining phases, (lid)2(hq), (lid)2(pyr), (lidhcl)2(hq), (lidhcl)2(res), and (lidhcl)2(pyr) were obtained by direct recrystallisation from the oily liquid obtained in LAG experiments.

2.4. Powder X-ray Diffraction

PXRD patterns were measured on a Bruker D8 Advance Series II Vario diffractometer (Bruker, AXS, Karlsruhe, Germany) using Cu-Kα1 radiation (λ = 1.5406 Å) at 40 kV and 40 mA. Diffraction patterns were collected over 2θ range of 5–60° and using a continuous step size of 0.02° and a total acquisition time of 1 h. The software used for data analysis was Diffrac.EVA v5.0 and TOPAS v6.0 (Bruker, AXS, Karlsruhe, Germany).

2.5. Single-Crystal X-ray Diffraction

2 by a full-matrix least-squares procedure using anisotropic displacement parameters [

Measured crystals were prepared under inert conditions immersed in perfluoropolyether as the protecting oil for manipulation. Suitable crystals were mounted on MiTeGen Micromounts™ (95 Brown Rd, Ithaca, NY, USA) and these samples were used for data collection. Data were collected with a Bruker D8 Venture diffractometer and processed with the APEX3 suite [ 14 ]. Structures were solved by direct methods [ 15 ], which revealed the position of all non-hydrogen atoms. These atoms were refined on Fby a full-matrix least-squares procedure using anisotropic displacement parameters [ 15 ]. All hydrogen atoms were located by difference Fourier maps and included as fixed contributions riding on attached atoms with isotropic thermal displacement parameters 1.2 times those of the respective atom. Geometric calculations and molecular graphics were performed with Mercury [ 16 ] and Olex2 [ 17 ]. Additional crystal data are shown in Table 1

2.6. Thermal Analysis

For the DSC/TGA experiments, samples in the range of 30 mg were studied using a Mettler Toledo TGA/DSC 3+ Star analyser. Samples were heated at 10 °C/min in the temperature range 25–190 °C under a nitrogen atmosphere with 100 mL/min flow in aluminium capsules.

2.7. Fourier-Transform Infrared Spectra

Fourier-transform infrared spectra (FTIR) were recorded with an attenuated total reflectance (ATR) accessory diamond crystal using an Invenio R FTIR spectrometer (Bruker). FTIR spectra were recorded within the wavenumber range from 4000 cm−1 to 400 cm−1 at 2 cm−1 resolution. In order to correctly subtract the background and, hence, obtain less noisy spectra, the solvent (0.9% NaCl water solution) was used at room temperature for the background measurement.

2.8. Solubility Assays

2(res) and (lidhcl)2(hq) that the cocrystal form remained stable after 24 h but not for (lidhcl)2(pyr). A calibration curve was built with different (lidhcl) concentrations [

R

2 values greater than 0.99, which were used to calculate the thermodynamic solubility. The peak used for the calibration curves was the area between 1712 cm−1 and 1612 cm−1, corresponding to (lidhcl), where there was no interference of any coformer.

Thermodynamic solubility measurements were performed in an Invenio R FTIR spectrometer (Bruker) after equilibrating the solids in a 0.9% NaCl water solution [ 8 ] under stirring at 500 rpm for 24 h. After the equilibrating time, the suspensions were filtrated through a 20 µm filter, and the resulting clear solution was analysed by FTIR. Then, the solid was analysed by PXRD to study the phase stability after equilibrium, resulting for (lidhcl)(res) and (lidhcl)(hq) that the cocrystal form remained stable after 24 h but not for (lidhcl)(pyr). A calibration curve was built with different (lidhcl) concentrations [ 18 19 ] obtaining linear models withvalues greater than 0.99, which were used to calculate the thermodynamic solubility. The peak used for the calibration curves was the area between 1712 cmand 1612 cm, corresponding to (lidhcl), where there was no interference of any coformer.

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