Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic,Kinetic and Environmental Aspects

Purpose

Amorphous solid dispersions (ASDs) have been widely used in the pharmaceutical industry for solubility enhancementof poorly water-soluble drugs. The physical stability, however, remainsone of the most challenging issues for the formulation development.Many factors can affect the physical stability via different mechanisms, and therefore an in-depth understanding on these factors isrequired.

Methods

In this review, we intend to summarize the physical stability of ASDsfrom a physicochemical perspective whereby factors that can influence the physical stability areclassified into thermodynamic, kinetic and environmental aspects.

Results

The drug-polymer miscibility and solubility are consideredas the main thermodynamicfactors which may determine the spontaneity of the occurrence of the physical instabilityof ASDs. Glass-transition temperature,molecular mobility, manufacturing process,physical stabilityof amorphous drugs, and drug-polymerinteractionsareconsideredas the kinetic factors which areassociated with the kinetic stability of ASDs on aging. Storage conditions including temperature and humidity could significantly affect the thermodynamicand kineticstabilityof ASDs.

Conclusion

When designing amorphous solid dispersions, it isrecommended that these thermodynamic, kinetic and environmental aspects should be completely investigatedand compared to establish rationale formulations for amorphous solid dispersions with high physical stability.

     

Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid

Purpose

The overall purpose of this study was to understand the impact of different biorelevant media types on solubility and crystallization from supersaturated solutions of model compounds (atazanavir, ritonavir, tacrolimus and cilnidipine). The first aim was to understand the influence of the lecithin content in FaSSIF. As the human intestinal fluids (HIFs) contain a variety of bile salts in addition to sodium taurocholate (STC), the second aim was to understand the role of these bile salts (in the presence of lecithin) on solubility and crystallization from supersaturated solutions,

Methods

To study the impact of lecithin, media with 3 mM STC concentration but varying lecithin concentration were prepared. To test the impact of different bile salts, a new biorelevant medium (Composite-SIF) with a composition simulating that found in the fasted HIF was prepared. The crystalline and amorphous solubility was determined in these media. Diffusive flux measurements were performed to determine the true supersaturation ratio at the amorphous solubility of the compounds in various media. Nucleation induction times from supersaturated solutions were measured at an initial concentration equal to the amorphous solubility (equivalent supersaturation) of the compound in the given medium.

Results

It was observed that, with an increase in lecithin content at constant STC concentration (3 mM), the amorphous solubility of atazanavir increased and crystallization was accelerated. However, the crystalline solubility remained fairly constant. Solubility values were higher in FaSSIF compared to Composite-SIF. Longer nucleation induction times were observed for atazanavir, ritonavir and tacrolimus in Composite-SIF compared to FaSSIF at equivalent supersaturation ratios.

Conclusions

This study shows that variations in the composition of SIF can lead to differences in the solubility and crystallization tendency of drug molecules, both of which are critical when evaluating supersaturating systems.

     

Investigation into the Emerging Role of the Basic Amino Acid L-Lysine in Enhancing Solubility and Permeability of BCS Class II and BCS Class IV Drugs

Background

The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need.

Purpose

In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed.

Methods

Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability. Chemical stability of quercetin-lysine and rutin-lysine was studied by assessing antioxidant capacity using Trolox and CUPRAC assays.

Results and Conclusion

Drugs-lysine salt/complexes were confirmed. Solubility enhancement factors ranged from 68- to 433-fold increases and dissolution rates were also significantly enhanced by up to 6-times, compared with drugs alone. With the exception of rutin-lysine, P_app for bendazac-lysine and quercetin-lysine enhanced by 2.3- to 4-fold. P_app for quercetin (Class IV) benefited more than bendazac (Class II) when complexed with lysine. This study warrants the use of L-lysine as a promising excipient for enhanced solubility and permeability of Class II and Class IV, providing that the solubility of the drug is ensured at ‘the door step’ of absorption sites.

     

Characterization of Supersaturated Danazol Solutions – Impact of Polymers on Solution Properties and Phase Transitions

Purpose

Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated.

Methods

A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior.

Results

Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 μg/mL, with the maximum effectiveness being reached at 10 μg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase.

Conclusions

The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.

     

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy

Purpose

To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods.

Method

Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy.

Results

Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage.

Conclusions

SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.

     

The Study of the Influence of Formulation and Process Variables on the Functional Attributes of Simvastatin–Phospholipid Complex

Purpose

The aim of the present study was to examine the influence of the formulation and process variables on the entrapment efficiency of simvastatin–phospholipid complex (SPC), prepared with a goal of improving the solubility and permeability of simvastatin.

Methods

The SPC was prepared using a solvent evaporation method. The influence of formulation and process variables on simvastatin entrapment was assessed using a central composite design. An additional SPC was prepared using the optimized variables from the developed quadratic model. This formulation was characterized for its physical–chemical properties. The functional attributes of the optimized SPC formulation were analyzed by apparent aqueous solubility analysis, in vitro dissolution studies, dissolution efficiency analysis, and ex vivo permeability studies.

Results

The factors studied were found to significantly influence the entrapment efficiency. The developed model was validated using the optimized levels of formulation and process variables. The physical–chemical characterization confirmed a formation of the complex. The optimized SPC demonstrated over 25-fold higher aqueous solubility of simvastatin, compared to that of pure simvastatin. The optimized SPC exhibited a significantly higher rate and extent of simvastatin dissolution (>98 %), compared to that of pure simvastatin (～16 %). The calculated dissolution efficiency was also found to be significantly higher for the SPC (～54 %), compared to that of pure simvastatin (～8 %). Finally, the optimized SPC exhibited a significantly higher simvastatin permeability (>78 %), compared to that of pure simvastatin (～11 %).

Conclusion

The present study shows that SPC can be a promising strategy for improving the delivery of simvastatin and similar drugs with low aqueous solubility.

     

Influence of Low-Molecular-Weight Excipients on the Phase Behavior of PVPVA64 Amorphous Solid Dispersions

Purpose

The oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved by the preparation of amorphous solid dispersions (ASDs) where the API is dissolved in polymeric excipients. Desired properties of such ASDs like storage stability, dissolution behavior, and processability can be optimized by additional excipients. In this work, the influence of so-called low-molecular-weight excipients (LMWEs) on the phase behavior of ASDs was investigated.

Method

Binary ASDs of an amorphous API, naproxen (NAP) or acetaminophen (APAP), embedded in poly-(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) were chosen as reference systems. Polyethylene glycol 1500 (PEG1500), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000), propylene glycol monocaprylate type II (Capryol? 90), and propylene glycol monolaurate type I (Lauroglycol? FCC) were used as LMWEs. The API solubility in the excipients and the glass-transition temperature of the ASDs were modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Kwei equation, respectively, and compared to corresponding experimental data.

Results

The API solubility curves in ternary systems with 90/10 wt%/wt% PVPVA64/LMWE ratios were very close to those in pure PVPVA64. However, the glass-transition temperatures of API/PVPVA64/LMWE ASDs were much lower than those of API/PVPVA64 ASDs. These effects were determined experimentally and agreed with the predictions using the PC-SAFT and Kwei models.

Conclusion

The impact of the LMWEs on the thermodynamic stability of the ASDs is quite small while the kinetic stability is significantly decreased even by small LMWE amounts. PC-SAFT and the Kwei equation are suitable tools for predicting the influence of LMWEs on the ASD phase behavior.

     

Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid

Purpose

Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH???pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state.

Methods

Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated.

Results

The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed.

Conclusions

The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.

     

Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations

Purpose

The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.

Methods

The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.

Results

Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.

Conclusions

Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.

     

Long-Acting Phospholipid Gel of Exenatide for Long-Term Therapy of Type II Diabetes

Purpose

This study aimed to develop a sustained-release formulation of exenatide (EXT) for the long-term therapeutic efficacy in the treatment of type II diabetes.

Methods

In this study, we present an injectable phospholipid gel by mixing biocompatible phospholipid S100, medium chain triglyceride (MCT) with 85% (w/w) ethanol. A systemic pre-formulation study has been carried out to improve the stability of EXT during formulation fabrication. With the optimized formulation, the pharmacokinetic profiles in rats were studied and two diabetic animal models were employed to evaluate the therapeutic effect of EXT phospholipid gel via a single subcutaneous injection versus repeated injections of normal saline and EXT solution.

Results

With optimized formulation, sustained release of exenatide in vivo for over three consecutive weeks was observed after one single subcutaneous injection. Moreover, the pharmacodynamic study in two diabetic models justified that the gel formulation displayed a comparable hypoglycemic effect and controlled blood glucose level compared with exenatide solution treated group.

Conclusions

EXT-loaded phospholipid gel represents a promising controlled release system for long-term therapy of type II diabetes.

     

Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures

Purpose

Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried.

Methods

Isomalt was freeze-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form of isomalt after freeze-drying and observe any changes occurring during storage in three different relative humidity conditions.

Results

Isomalt was successfully transformed into the amorphous form with freeze-drying and three diastereomer combinations remained stable as amorphous during storage; one of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties.

Conclusions

Isomalt was shown to be a suitable excipient for freeze-drying. Preferably a mixture of the diastereomers should be used, as the mixture containing only one of the isomers showed physical instability. A mixture containing a 1:1 ratio of the two diastereomers showed the best physical stability in the amorphous form.

     

Inclusion Complexes of Nateglinide with HP–β–CD and L-Arginine for Solubility and Dissolution Enhancement: Preparation,Characterization, and Molecular Docking Study

Purpose

The objective of present study was to increase solubility and dissolution performance of a poorly water soluble antidiabetic drug, Nateglinide (NAT), through formation of inclusion complexes with hydroxypropyl-beta-cyclodextrin (HP–β–CD). The effect of L-arginine (ARG), an amino acid, on the complexation efficiency and solubility enhancing power of HP–β–CD was investigated by preparing ternary inclusion complexes.

Methods

The binary and ternary inclusion complexes were prepared by physical mixing, kneading, co-evaporation, and spray drying methods containing NAT, HP–β–CD, and ARG. The complexes were characterized by FTIR, DSC, PXRD, and ¹H–NMR. Molecular modeling study revealed that introduction of ternary agent ARG have improved the interactions of NAT and HP–β–CD.

Results

The complex prepared by spray drying method showed the highest increase in solubility and dissolution rate compared to other methods. Molecular docking study revealed that ARG interactions plays an essential role in increasing the stability and solubility of the complex.

Conclusions

The present study demonstrated increase in solubility and dissolution of NAT. Hence, ternary complexes of NAT can be used as an efficient tool for the delivery of insoluble drug, NAT.

     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> Skin Retention and Drug Permeation through Intact and Microneedle Pretreated Skin after Application of Propranolol Loaded Microemulsions

Purpose

Topical beta-blockers are efficacious for treating infantile hemangiomas, but no formulations have been specifically optimized for skin delivery. Our objective was to quantify skin concentrations and drug permeation of propranolol (a nonselective beta-blocker) after application of microemulsions to intact and microneedle pretreated skin.

Methods

Four propranolol-loaded microemulsions were characterized for droplet size, surface charge, conductivity, pH, drug solubility, and drug release. Skin concentrations and drug permeation through skin were quantified using LC-MS. Skin-to-receiver ratios were used to compare the microemulsion formulations to a drug-in-PBS solution.

Results

Propranolol solubility was significantly greater in microemulsions vs PBS. Cumulative drug release from the microemulsions over 24 h ranged from 13 to 26%. Skin concentrations and drug permeation through intact skin was significantly higher from PBS; however, the skin-to-receiver ratios were significantly higher for water-rich microemulsions compared to PBS or surfactant-rich microemulsions. Microneedle pretreatment significantly increased skin concentrations for all formulations. Skin-to-receiver ratios significantly increased after microneedle pretreatment for surfactant-rich microemulsions.

Conclusions

Microemulsion formulation can be altered to elicit different drug delivery profiles through MN-treated skin. This could be advantageous for maximizing local skin drug concentrations and improving dosing schedules for infantile hemangioma treatment.

     

Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions

Purpose

Tacrolimus, an immunosuppressant, is a poorly water soluble compound whereby the commercially available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystallization following storage at stress conditions.

Methods

Products were purchased from a pharmacy and stored at 40°C/75% relative humidity (RH), open dish conditions. Crystallinity was determined using X-ray diffraction. The quantity of the ingredients in the formulations were determined using different approaches and the various factors that might cause instability in the formulations were studied.

Results

After 4 weeks of open dish storage at 40°C/75% RH, one of the generic formulations showed evidence of tacrolimus crystallization. Further investigations revealed batch-to-batch variations in crystallization tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystallization was also observed at lower storage temperatures (30°C) when the RH was maintained at 75%. It was found that crystallization could be induced in a model formulation by wet granulating an ethanolic solution of the drug with lactose and drying at 60–70°C followed by exposure to stress conditions.

Conclusions

It seems probable that the generic that was susceptible to crystallization contains amorphous drug physically mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufacturing process on the stability of the resultant amorphous product.

     

Stabilization of HAC1 Influenza Vaccine by Spray Drying: Formulation Development and Process Scale-Up

Purpose

Stable vaccines with long shelf lives and reduced dependency on the cold chain are ideal for stockpiling and rapid deployment during public emergencies, including pandemics. Spray drying is a low-cost process that has potential to produce vaccines stable at a wide range of temperatures. Our aim was to develop a stable formulation of a recombinant H1N1 influenza hemagglutinin vaccine candidate and take it to pilot-scale spray-drying production.

Methods

Eight formulations containing different excipients were produced and assayed for antigen stability, powder characteristics, and immunogenicity after storage at a range of temperatures, resulting in the identification of four promising candidates. A pilot-scale spray-drying process was then developed for further testing of one formulation.

Results

The pilot-scale process was used to reproducibly manufacture three batches of the selected formulation with yields >90%. All batches had stable physical properties and in vitro potency for 6 months at temperatures from ?20°C to +50°C. Formulations stored for 3 months elicited immunogenic responses in mice equivalent to a frozen lot of bulk vaccine used as a stability control.

Conclusions

This study demonstrates the feasibility of stabilizing subunit vaccines using a spray-drying process and the suitability of the process for manufacturing a candidate product.

     

The Use of Surfactants to Solubilise a Glucagon Analogue

Purpose

The peptide hormone glucagon, used to treat hypoglycaemic incidents, is prone to aggregation. Generating alternatives with better stability is of pharmaceutical interest in the treatment of diabetes. Here we investigate the impact of six different surfactants on the solubility and stability of ZP-GA-1, a stable version of glucagon.

Methods

We use chemical surfactants (sodium dodecyl sulphate, dodecyl maltoside and polysorbate 20) and the biosurfactants rhamnolipid, sophorolipid and surfactin. We investigate their interaction with ZP-GA-1 by pyrene fluorescence, circular dichroism and isothermal titration calorimetry.

Results

All six surfactants induce α-helical structure in ZP-GA-1, SDS having the biggest impact and polysorbate 20 the smallest. SDS keeps ZP-GA-1 solubilised over &gt;48 days as opposed to 29 days in DDM, 3 days in polysorbate 20 and 0 days in buffer. Similarly, much less SDS than DDM, polysorbate 20 or biosurfactant is needed to redissolve aggregated ZP-GA-1. ITC confirms this trend, with SDS exhibiting very strong, and polysorbate 20 very weak interactions.

Conclusion

Simple surfactant structures promote stronger peptide interactions. ITC shows promise as a general strategy to predict surfactants’ solubilising powers. Stronger enthalpic interactions improved the absolute solubility of ZP-GA-1 and their strength correlated to the absolute solubility of the peptides though not to the kinetics of precipitation.

     

Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in Supersaturated Solutions of Atazanavir

Purpose

The goals of this study were to determine: 1) the impact of surfactants on the “amorphous solubility”; 2) the thermodynamic supersaturation in the presence of surfactant micelles; 3) the mechanism of solute solubilization by surfactant micelles in supersaturated solutions.

Methods

The crystalline and amorphous solubility of atazanavir was determined in the presence of varying concentrations of micellar sodium dodecyl sulfate (SDS). Flux measurements, using a side-by-side diffusion cell, were employed to determine the free and micellar-bound drug concentrations. The solubilization mechanism as a function of atazanavir concentration was probed using fluorescence spectroscopy. Pulsed gradient spin-echo proton nuclear magnetic resonance (PGSE-NMR) spectroscopy was used to determine the change in micelle size with a change in drug concentration.

Results

Changes in the micelle/water partition coefficient, K _m/w , as a function of atazanavir concentration led to erroneous estimates of the supersaturation when using concentration ratios. In contrast, determining the free drug concentration using flux measurements enabled improved determination of the thermodynamic supersaturation in the presence of micelles. Fluorescence spectroscopic studies suggested that K _m/w changed based on the location of atazanavir solubilization which in turn changed with concentration. Thus, at a concentration equivalent to the crystalline solubility, atazanavir is solubilized by adsorption at the micelle corona, whereas in highly supersaturated solutions it is also solubilized in the micellar core. This difference in solubilization mechanism can lead to a breakdown in the prediction of amorphous solubility in the presence of SDS as well as challenges with determining supersaturation. PGSE-NMR suggested that the size of the SDS micelle is not impacted at the crystalline solubility of the drug but increases when the drug concentration reaches the amorphous solubility, in agreement with the proposed changes in solubilization mechanism.

Conclusions

Micellar solubilization of atazanavir is complex, with the solubilization mechanism changing with differences in the degree of (super)saturation. This can result in erroneous predictions of the amorphous solubility and thermodynamic supersaturation in the presence of solubilizing additives. This in turn hinders understanding of the driving force for phase transformations and membrane transport, which is essential to better understand supersaturating dosage forms.

     

Valvejet Technology for the Production of a Personalised Fixed Dose Combination of Ramipril and Glimepiride: an Investigative Study on the Stability of Ramipril

Purpose

To use valvejet technology for printing a fixed dose combination of ramipril and glimepiride, and to investigate the stability profile of ramipril, which is susceptible to a range of processing and storage conditions.

Methods

Inks of ramipril and glimepiride were formulated and printed on to HPMC film and the films were evaluated for the chemical and solid-state integrity of the APIs using HPLC and XRPD. The stability of the APIs in the inks and in the printed samples was investigated using Raman and NMR techniques.

Results

The printed samples demonstrated excellent precision and accuracy in the doses of APIs deposited. Both drugs were chemically intact in the freshly printed samples and ramipril was found to be in its amorphous form. Ramipril in the printed samples has transformed into ramipril diketopiperazine when stored at 40°C with 75% RH, but remained stable when stored in a desiccator. Results from the stability study of ramipril ink show that the API has undergone degradation when stored both at room temperature and at 40°C but remained stable when stored in a refrigerator.

Conclusion

An FDC of ramipril and glimepiride was successfully printed using valvejet technology. The significance of inkjet printing in producing amorphous dosage forms from solution based inks and personalised dosage forms of drugs susceptible to processing conditions was demonstrated using ramipril. This study illustrates the significance of examining the stability of the APIs in the inks and the importance of appropriate storing of both the inks and printed samples.

     

Electrosprayed Myocet-like Liposomes: An Alternative to Traditional Liposome Production

Purpose

Although doxorubicin (DXR) has been on the market for many years as an anti-cancer drug, a number of serious dose-limiting toxicities hinder its widespread use. To reduce the known toxicities of soluble DXR, various liposomes have been designed including Doxil, Caelyx, and Myocet. Myocet, a non-PEGylated liposomal formulation containing DXR, was found to reduce the toxicities associated with soluble DXR and has been used in Europe and Canada (but not the US) as a first line therapy. While regarded as successful, Myocet does have some formulation drawbacks including stability, drug release, and an arduous formulation and remote loading method for preparation.

Methods

Our lab has developed a liposomal electrospray process in which formulation and remote loading occurs continuously in one step, cutting down on the total time of production and increasing the drug retention in the liposomes with respect to more conventional methods. Electrosprayed Myocet-like liposomes were then tested in vitro for release kinetics and cytotoxicity with respect to a more conventional formulation method.

Results

Myocet-like liposomes manufactured via electrospray had similar DXR loadings, hydrodynamic diameters, morphologies, and cytotoxic profiles as their thin-film hydration counterparts, but their release profiles were drastically prolonged.

Conclusions

Our findings indicate that electrospray is a viable manufacturing procedure to scalably produce Myocet-like liposomes that appear to be more stable than those formulated through thin-film hydration.

     

Preparation and Evaluation of Palm Oil-Based Polyesteramide Solid Dispersion for Obtaining Improved and Targeted Dissolution of Mefenamic Acid

Purpose

The aim of this work was to investigate the functional role of newly synthesised palm oil-based polyesteramide (POPEA) and stearic acid-based polyesteramide (SAPEA) in mefenamic acid (MA) solid dispersion (SD).

Methods

Solid dispersions of MA were prepared by hot melt method, using a combination of POPEA/SAPEA as a polymer carrier. The effects of POPEA/SAPEA mixture ratio, drug loading percentage and influence of different Mw of POPEA (4000–17,000 Da) in SD were investigated. The SDs were characterised for drug content, solubility, dissolution behaviour and physico-chemical characteristics by DSC and FTIR. Comparisons were made with pure drug, physical mixture and a marketed MA formulation.

Results

All SDs demonstrated faster dissolution rate than pure MA and SD 6 formulated with SAPEA/POPEA 4000 Da, 8:2 showed the highest T ₅₀ release rate (45 min) with no significant difference (P?>?0.05) compared to marketed formulation. All SDs showed improved drug release (85.48?±?1.17 to 90.66?±?1.53%) against marketed formulation (81.30?±?1.26%) and MA (56.27?±?1.08%) after 6 h of dissolution. DSC endothermic peak for MA in SD 6 was broadened and shifted to lower temperature (194 °C). FTIR spectroscopy confirmed no chemical changes in MA SD, but establishment of hydrogen bonding between hydroxyl groups of PEA with amine groups of MA was observed by the red shift of OH band in SD samples. The SD was stable (P?>?0.05) at ambient condition for up to 90 days, reflecting by the drug content, dissolution profiles and solubility of the formulation.

Conclusions

POPEA demonstrated surface lowering and wettability effects in improving the aqueous solubility and dissolution rate of MA in SD. The crystalline drug was transformed to amorphous formulation, via solubilisation and crystallisation inhibition effect of the PEA.