Solid Dispersion & Eutectic Mixtures for Solubility & Dissolution Rate Modification

Solid eutectic mixture A simple eutectic mixture consists of two components which are completely miscible in liquid state but to a limited extend in solid state. These are prepared by rapid solidification of fused melt of two components. When a mixture of poor water soluble drug and water soluble carrier is dissolved in aqueous medium, the carrier is dissolved rapidly, releasing very fine crystal of drug. Solid solution In a solid solution, the two components crystallize together in a homogeneous one phase system. The particle size of the drug in the solid solution is reduced to its molecular size responsible for increase in dissolution rate. On the extend of miscibility of two components, solid solution is classified as continuous and discontinuous. In continuous solid solution, the two components are miscible in the solid state in all proportions. In discontinuous solid solutions, the solubility of each of the components in the other component is limited. Ref.: Int J Pharm Investig. 2012 Jan-Mar; 2(1): 12–17

Ref.: Physical Pharmacy Book, 6 th Ed.

Example 1 Fusion Method for Solubility and Dissolution Rate Enhancement Using Block Copolymer Poloxamer 407 AAPS PharmSciTech (# 2016), DOI: 10.1208/s12249-016-0482-6 Fusion method for making solid dispersions and eutectic mixtures of poorly soluble drugs with hydrophilic polymers has been used widely in the past for solubility enhancement and possible improvement in bioavailability of these drugs. It involves the use of polymers (e.g., Poloxamers , some grades of polyethylene glycols) which melt at relatively low temperatures (60–90°C) . This technique allows mixing of drug and polymer at a molecular level without the use of organic solvents. Major advantages of this method are absence of the risk of residual solvents unlike other solid dispersion techniques involving use of solvents, easy processing in terms of drying, and improved miscibility of drug and polymer at relatively low temperatures .

Stability of formulations and drug-polymer miscibility can be predicted from the change in Gibb’s energy upon polymer-drug mixing. The first step in the solid dispersions and eutectic mixtures formation is the melting of drug and polymer at their respective melting points. Secondly, the molten drug and polymer are uniformly mixed. Thirdly, the molten mixture is cooled down to room temperature to get a solid product. In case of eutectic mixtures, the melting point of the mixture is less than the individual components which means less energy is required for the first step and hence higher solubility and miscibility.

Solid dispersion and eutectic formation affects the solubility and /or the dissolution rate. Intrinsic or saturation solubility of drug and its dissolution are two different processes. Although dissolution behavior of any dosage form depends a lot on the former parameter, dissolution is a kinetic phenomenon whereas saturation solubility is a thermodynamic phenomenon. By saying kinetic phenomenon, it means that dissolution behavior depends on how a drug molecule after getting solubilized bypasses the diffusion layer of saturated drug solution into the bulk media and remain solubilized there until it gets Absorbed.

Preparation of Physical Mixtures and Binary Fused Mixtures Physical mixtures were prepared with drug to polymer ratios: 1:0.25, 1:0.5, and 1:0.75 w/w, respectively. A lab-scale high shear mixer was used for carrying out the fusion process, and fusion was carried until a product temperature of 70 ± 1.2°C was attained. Mixing was carried out until fusion was completed. Mixture was cooled down by rapidly circulating water at 25.0 ± 1.0°C through the water jacket. The solidified mixture was scrapped out, then powdered with a mill using a mesh of 1680 μm opening. All the samples were collected and stored in tightly sealed containers in a desiccator at a temperature of 25 ± 1.8°C for further analysis.

Particle Size Analysis Figure 3 shows the particle size distribution of the prepared binary fusion mixtures for all the polymer ratios. Most of the particles were below the size of 500 μm. It was clearly seen that with the increase in the polymer ratio, there was a greater fraction of larger particles. Fig. 3. Particle size analysis of fusion mixtures (FM)

Saturation Solubility Studies Saturation solubility enhancement was found for the PMs as well as the FMs for all the aqueous media used in the study as seen in Fig. 4. The effect was most pronounced in acidic media where, solubility enhancement was 18-fold for FM 1:0.75 as compared to ibuprofen. In water, it was a 5-fold increase. Fig. 4. Saturation solubility studies in de-ionized water and 0.1 N HCl (pH = 1.2)

In acidic media, almost 58% cumulative drug release for FM 1:0 In acidic media, almost 58% cumulative drug release for FM 1:0.75 was encountered whereas for drug, it was only 3.67% after 60 min. Fig. 6. In vitro dissolution studies for ibuprofen, physical mixtures (PM), and fusion mixtures (FM) in 0.1 N HCl (pH = 1.2).

Example 2 Pharmaceutical Applications of Solid Dispersion Systems: Dissolution of Griseofulvin-Succinic Acid Eutectic Mixture J Pharm Sci. 1976 Aug;65(8):1212-4 Dissolution Rate Studies Solid dispersions containing 2.5,5, 10, 25, and 55% (eutectic composition) of griseofulvin' in the griseofulvin succinic Acid system were prepared by the fusion method. They were pulverized with a mortar and pestle, and the 60-100-mesh fraction was collected. The same mesh sizes of succinic acid were prepared after fusion and resolidification. The solid-dispersed samples containing 5 mg of griseofulvin were used in each study in 500 ml of distilled water at 37deg. The amount of griseofulvin dissolved was monitored spectrophotometrically at 295 nm. The dissolution rate of succinic acid (45 mg) from various sizes of powder was measured spectrophotometrically at 195 nm.

Fluorometric assay was employed because of its high sensitivity, since griseofulvin concentrations obtained from the tablet study were too low to be measured by the UV spectrophotometric method. Both succinic acid and succinic anhydride were found not to interfere with the griseofulvin analysis All dissolution studies were conducted at least in duplicate, and highly reproducible results were always achieved. Only the average values are reported.

From another study

Example 3 Intranasal Eutectic Powder of Zolmitriptan with Enhanced Bioavailability in the Rat Brain Molecular Pharmaceutics, 2016 , DOI: 10.1021/acs.molpharmaceut.6b00453 Introduction Eutectic mixtures of drugs are recognized for their ability to enhance drug transport across membranes. This report describes formulation of an antimigraine agent as a eutectic with a pharmaceutically inert co-former. The formulation is intended for presentation as a dry powder to be instilled into the nostrils for rapid onset of action against migraine attacks.

Why intranasal route? Currently, three types of formulations of zolmitriptan are available in the market; conventional oral tablets, orally disintegrating tablets, and nasal liquid sprays. During a migraine attack, accompanying nausea and vomiting are the main problems due to which a patient may not be willing to take the medication orally. Why dry powder? Nasal sprays (Zomig® and Imigran®) are available, but these have limitations. Intra-nasal administration of liquid sprays often results in run-down to the oesophagus and perception of bitter taste, poor bioavailability and a bimodal absorption profile. The chemical stability of drugs in solution during shelf life is an issue and the volume of liquid required to administer the prescribed dose is inconvenient. Liquid nasal sprays have short residence time (15-20 min) in the nasal cavity due to rapid mucociliary clearance. Upon instillation of liquid formulations, the mucus in the nasal mucosa gets diluted locally, runs down the nasal cavity into the pharynx and is swallowed.

Why eutectic mixture? Since residence time in the nasal cavity is short, rapid dissolution and a high concentration gradient across the nasal mucosa are crucial to drug bioavailability. Both criteria can be met by formulating a eutectic system of crystalline drugs with a suitable excipient. Thus, the basis of work of the current research focuses on the formulation of a novel dosage form of zolmitriptan for brain targeting through the intranasal route. In addition to providing a better deposition profile, longer residence time and high concentration gradient locally at the absorption site, higher storage stability may be expected in comparison to liquid formulations.

Objective A eutectic of zolmitriptan with nicotinamide as coformer was formulated to realize the well-known advantages of eutectics. The formulation was characterised using different characterizing techniques such as DSC, FTIR, and PXRD. Biodistribution studies were also conducted with intravenous (IV) solution, IN pure zolmitriptan powder, and IN eutectic formulation. Materials Zolmitriptan, Nicotinamide, …

Screening for formation of eutectic Zolmitriptan and three coformers-- citric acid, tartaric acid and nicotinamide were taken in different stoichiometric ratios and ground in a mortar-pestle for different periods up to 20 minutes. Zolmitriptan formed a pasty mass upon trituration with citric and tartaric acids in all proportions, while a free flowing powder was obtained with nicotinamide in 1:1 proportion. The resultant mixtures were subjected to differential scanning calorimetry. Accurately weighed samples (3-5 mg) were placed in standard sealed aluminium pans. The temperature range for the thermogram was 40 to 300°C, and the samples were heated at a rate of 10°C/min.

DSC Results Zolmitriptan exhibited a sharp melting point at 137 DSC Results Zolmitriptan exhibited a sharp melting point at 137.7˚C, while nicotinamide melted at 128.9°. The eutectic had its melting point at 102.4°C as depicted in Fig. 1A. The absence of additional melting point peaks in DSC indicated that there was no further transformation to cocrystals or residual unreacted solid phase in the eutectic. Fig. 1 (A): DSC overlay of melting endotherms of nicotinamide, zolmitriptan and eutectic at 0.5 mole fraction indicating melting point and enthalpy of fusion.

DSC thermograms (Fig. 1B) show the eutectic melting endotherm at 102˚C for all the mole fractions of zolmitriptan and nicotinamide that were examined. Additional melting endotherms (at 118˚C and 123˚C) were obtained with zolmitriptan mole fraction of 0.25 and 0.75 respectively. Fig. 1 (B): DSC Overlaid thermograms of triturated mixtures of zolmitriptan and nicotinamide in different mole fractions of zolmitriptan: nicotinamide (1):0.25, (2): 0.33, (3): 0.5, (4): 0.66, (5): 0.75.

Dissolution Dissolution was studied in a six-vessel paddle stirred USP dissolution apparatus II. Each dissolution vessel contained 900 ml of 0.1 N HCl, stirred at a constant speed of 50 rpm. The contents of the dissolution beakers were thermostatted at 37˚C. Samples of zolmitriptan powder or eutectic formulation were sieved through a 30 μm mesh and accurately weighed amounts transferred into dissolution vessels. Dissolution was studied up to 1 h. At specific intervals, 5 mL of the dissolution medium was withdrawn and replaced by an equal volume of fresh medium to maintain a constant volume. The concentration of the aliquots was determined with appropriate dilutions using HPLC.

End Dissolution Results The dissolution rates of zolmitriptan and its eutectic with nicotinamide are depicted in Fig. 5 Zolmitriptan has poor aqueous solubility, but the eutectic formulation showed approximately 80% dissolution within the first 5 min. In comparison, zolmitriptan powder exhibited <60% dissolution in the same time. The eutectic likely showed faster dissolution because of weaker adhesive intermolecular interactions across solid-solid interfaces in the eutectic microstructure as compared to cohesive intereactions in crystalline zolmitriptan. Fig. 5. Dissolution profile of zolmitriptan powder (squares) and 1:1 eutectic powder (circles) End