Crystallization and Rheology of Mono- and Diglycerides and Their Role in Stabilization of Emulsion Droplets in Model Topical Ointments.

The crystallization behavior of commercial mono- and diglycerides (MDG) in paraffin oil is studied to develop an in-depth understanding of the polymorphic transitions useful for the physical stability of petroleum oil-based topical emulsions. Optical microscopy and differential scanning calorimetry measurements showed the formation of plate-like and spherulite crystals at high and low temperatures, in sequence, while cooling a solution of MDG dissolved in oil. High-resolution NMR and X-ray scattering demonstrate that 1-monoglycerides (mixture of 1-glyceride monostearate and 1-glyceride monopalmitate) cocrystallize to an inverse-lamellar structure (Lα polymorph) that mainly forms plate-like crystals at a higher temperature. The Lα polymorph is seen to exist up to room temperature during the cooling process. At lower temperatures, 1,3-diglycerides (mixture of 1,3-glyceryl distearate and 1,3-glyceryl dipalmitate) crystallize into ß-polymorphs that form spherulites. The spherulites tend to assemble into elongated strands via aggregation, leading to the formation of a percolating network structure. The sizes of both types of crystals decrease with an increasing cooling rate, leading to a higher mechanical modulus due to the increased network connectivity of spherulites. In an emulsion, monoglycerides in the form of Lα polymorphs having plate-like crystal morphology show a higher affinity to the polar liquid/oil interface, thereby providing better interfacial stability compared to the spherulitic ß-polymorphs. However, diglycerides in the form of spherulites form bulk network structures which provide network stabilization to the suspended droplets. This work demonstrates that MDG, a commercially available ingredient that combines the differential functionality of monoglycerides and diglycerides, is an effective, bifunctional, emulsifying agent for petrolatum-based topical emulsions.

Delineating the role of cooperativity in the design of potent PROTACs for BTK.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.

The Effect of Process Parameters on the Microstructure, Stability, and Sensorial Properties of an Emulsion Cream Formulation.

A classical emulsion formulation based on petrolatum and mineral oil as the internal phase with emulsifier wax as a typical topical emulsion cream was investigated for the effect of process parameters on drug product quality and performance attributes. The Initial Design of Experiment (DoE) suggested that an oil phase above 15%, coupled with less than 10% emulsifying wax, resulted in less stable emulsions. Different processing parameters such as homogenization speed, duration, cooling rate, and final temperature showed minimal influence on properties and failed to improve stability. The final DoE suggested that the optimal emulsion stability was achieved by introducing a holding period midway through the cooling stage after solvent addition. Within the studied holding temperature range (25-35 °C), a higher holding temperature correlated with increased emulsion stability. However, the application of shear during the holding period, using a paddle mixer, adversely affected stability by disrupting the emulsion microstructure. IVRT studies revealed that the release of lidocaine was higher in the most stable emulsion produced at a holding temperature of 35 °C compared to the least stable emulsion produced at a holding temperature of 25 °C. This suggests that a holding temperature of 35 °C improves both the stability and active release performance. It appears that a slightly higher holding temperature, 35 °C, allows a more flexible and stable emulsifying agent film around the droplets facilitating stabilization of the emulsion. This study offers valuable insights into the relationship between process parameters at various stages of manufacture, microstructure, and various quality attributes of emulsion cream systems. The knowledge gained will facilitate improved design and optimization of robust manufacturing processes, ensuring the production of the formulations with the desired critical quality attributes.

Assessing and Predicting Physical Stability of Emulsion-Based Topical Semisolid Products: A Review.

The emulsion-based topical semisolid dosage forms present a high degree of complexity due to their microstructures which is apparent from their compositions comprising at least two immiscible liquid phases, often times of high viscosity. These complex microstructures are thermodynamically unstable, and the physical stability of such preparations is governed by formulation parameters such as phase volume ratio, type of emulsifiers and their concentration, HLB value of the emulsifier, as well as by process parameters such as homogenizer speed, time, temperature etc. Therefore, a detailed understanding of the microstructure in the DP and critical factors that influence the stability of emulsions is essential to ensure the quality and shelf-life of emulsion-based topical semisolid products. This review aims to provide an overview of the main strategies used to stabilize pharmaceutical emulsions contained in semisolid products and various characterization techniques and tools that have been utilized so far to evaluate their long-term stability. Accelerated physical stability assessment using dispersion analyzer tools such as an analytical centrifuge to predict the product shelf-life has been discussed. In addition, mathematical modeling for phase separation rate for non-Newtonian systems like semisolid emulsion products has also been discussed to guide formulation scientists to predict a priori stability of these products.

Influence of Manufacturing Process on the Microstructure, Stability, and Sensorial Properties of a Topical Ointment Formulation.

The manufacturing process for ointments typically involves a series of heating, cooling, and mixing steps. Precise control of the level of mixing through homogenization and the cooling rate, as well as temperature at different stages, is important in delivering ointments with the desired quality attributes, stability, and performance. In this work, we investigated the influence of typical plant processing conditions on the microstructure, stability, and sensorial properties of a model ointment system through a Design of Experiments (DoE) approach. Homogenization speed at the cooling stage after the addition of the solvent (propylene glycol, PG) was found to be the critical processing parameter that affects stability and the rheological and sensorial properties of the ointment. A lower PG addition temperature was also found to be beneficial. The stabilization of the ointment at a lower PG addition temperature was hypothesized to be due to more effective encapsulation by crystallizing mono- and diglycerides at the lower temperature. The in vitro release profiles were found to be not influenced by the processing parameters, suggesting that for the ointment platform studied, processing affects the microstructure, but the effects do not translate into the release profile, a key performance indicator. Our systematic study represents a Quality-by-Design (QbD) approach to the design of a robust manufacturing process for delivering stable ointments with the desired performance attributes and properties.

Model for Long Acting Injectables (Depot Formulation) Based on Pharmacokinetics and Physical Chemical Properties.

The objective was to develop a model to a priori identify the most suitable depot technology for a candidate based upon its therapeutic index (TI), pharmacokinetics (PK), and physical chemical properties. A depot map of release rates needed to achieve target PK in TI against release rates predicted based on intrinsic dissolution rate (IDR) and particle size (PS) clearly identified three zones: (a) products and candidates around the line of identity for which suspension is the appropriate depot technology, (b) area to the right of line of identity in which depot candidates would require a controlled release technology such as PLGA microspheres since in vivo release rate needed for PK in TI is significantly lower than predicted based on IDR and PS, and (c) area to the left of the line of identity where IDR is not sufficient to achieve target in vivo release rate for PK in TI and hence enhanced dissolution is needed such as with nanoparticles. Dose-solubility technology map of approved depot products and candidates showed clusters of products around a depot technology such as suspensions and microspheres, for drugs with high dose/low solubility and low dose/high solubility compounds, respectively. Novel PK-based computational tool showed how all combinations of depot doses and release rate constants for a candidate can be calculated to achieve plasma levels within the TI bounded by minimum effective and minimum toxic concentrations (MEC and MTC). The PK predictions for several drugs such as estradiol, risperidone, medroxyprogesterone acetate (MPA), and ziprasidone showed how these predictions can guide scientists to target specific depot doses and release rates into the depot formulation. In parallel, IDR of depot compounds clearly showed differentiation of compounds by successful depot technologies to achieve target dose and duration. For drugs with IDR between 0.1 and 1 mg/h/cm2, aqueous suspension has successfully delivered depot PK profile, while for candidates with IDRs greater than 1 mg/h/cm2, controlled release technology such as microsphere or in situ gel was required. The framework, prediction tools, and depot map will reduce the need for semi-empirical formulation work and preclinical studies to design depot formulations. Graphical Abstract.

API-polymer interactions in Sepineo P600 based topical gel formulation- impact on rheology.

In the present study, topical gel and emulsion gel were formulated using Acrylamide/ Sodium Acryloyldimethyl taurate copolymer (Sepineo P600) as a gelling agent, and their rheological attributes and physical stability were evaluated upon incorporation of API. Lidocaine, a free base drug (pKa 7.92) was used as a model drug in all formulations. Medium- chain Triglycerides (MCT) was used as a dispersed phase to prepare the emulgel. Results show that the rheological properties of both gel and emulgel such as viscosity, elastic moduli and yield stress were significantly influenced by the pH of the topical formulations and API concentration. A lower pH (pH < pKa) leads to the increase in number of cationic species of lidocaine, which results in the weakening of the structure of the gel matrix by charge screening of polymer-polymer repulsions. Interactions between API and polymer chains through electrostatic attraction may play a major role in altering the rheology, which could potentially impact the physical stability against phase separation of the internal phase in emulsion gel samples. This study provides valuable insights into rheological behaviors of Sepineo P600 gel and emulgel which can be modified or tuned though the interplay of the API properties and critical formulation parameters such as pH. The tunable rheological properties with simpler manufacturing process make Sepineo P600 gel and emulsion gel very suitable systems for use in semisolid topical formulations.

Prediction of vitreal half-life based on drug physicochemical properties: quantitative structure-pharmacokinetic relationships (QSPKR).

PURPOSE: The aim of this study was to develop quantitative structure pharmacokinetic relationships (QSPKR) to correlate drug physicochemical properties (molecular weight, lipophilicity, and drug solubility), dose, salt form factor, and eye pigmentation factor to intravitreal half-life in the rabbit model. METHODS: Dataset derived from prior literature reports, which included molecules with complete structural diversity, was used to develop the QSPKR models. Entire dataset as well as subsets limited to albino rabbit data, pigmented rabbit data, acids, bases, zwitterions, neutral compounds, suspensions, and macromolecules were analyzed. Multiple linear regression analysis was carried out with noncollinear independent variables and the best-fit models were selected based on correlation coefficients and goodness of fit statistics. RESULTS: The analysis indicated that logarithm of MW (Log MW), lipophilicity (Log P or Log D) and dose number (dose/solubility at pH 7.4), are the most critical determinants of intravitreal half-life of the compounds analyzed. The best-fit models obtained from the entire dataset (Log t (1/2) = -0.178 + 0.267 Log MW - 0.093 Log D + 0.003 dose/solubility at pH 7.4 + 0.153 Pigmentation Factor and Log t (1/2) = -0.32 + 0.432 Log MW - 0.157 Log P + 0.003 dose/solubility at pH 7.4) predicted the various subsets well. Pigmented dataset and zwitterions were better predicted by Log P rather than Log D. CONCLUSIONS: The present study confirmed that intravitreal half-life could be better predicted by a group of variables (Log MW, Log P or Log D, dose number) rather than a single variable. In general, increasing Log MW and dose number, while reducing Log D or Log P would be beneficial for prolonging intravitreal half-life of drugs.

In vitro and in vivo characterization of amorphous, nanocrystalline, and crystalline ziprasidone formulations.

Ziprasidone, commercially available as Geodon capsules, is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. It is a BCS Class II drug that shows up to a 2-fold increase in absorption in the presence of food. Because compliance is a major issue in this patient population, we developed and characterized solubilized formulations of ziprasidone in an effort to improve absorption in the fasted state, thereby resulting in a reduced food effect. Three formulations utilizing solubilization technologies were studied: (1) an amorphous inclusion complex of ziprasidone mesylate and a cyclodextrin, (2) a nanosuspension of crystalline ziprasidone free base, and (3) jet-milled ziprasidone HCl coated crystals made by spray drying (CCSD) the drug with hypromellose acetate succinate. The formulations were characterized by in vitro methods appropriate to each particular solubilization technology. These studies confirmed that ziprasidone mesylate - cyclodextrin was an amorphous inclusion complex with enhanced dissolution rates. The ziprasidone free base crystalline nanosuspension showed a mean particle size of 274 nm and a monomodal particle size distribution. In a membrane permeation test, the CCSD showed a 1.5-fold higher initial flux compared to crystalline ziprasidone HCl. The three formulations were administered to fasted beagle dogs and their pharmacokinetics compared to Geodon capsules administered in the fed state. The amorphous complex and the nanosuspension showed increased absorption in the fasted state, indicating that solubilized formulations of ziprasidone have the potential to reduce the food effect in humans.

Effect of cyclodextrin derivation and amorphous state of complex on accelerated degradation of ziprasidone.

Inclusion complexes of ziprasidone with several ß-cyclodextrins [ß-CDs; sulfobutylether-ß-cyclodextrins (SBEßCD), hydroxypropyl-ß-cyclodextrins (HPßCD), methyl-ß-cyclodextrins (MßCD), and carboxyethyl-ß-cyclodextrins (CEßCD)] were prepared and solution stability was evaluated at elevated temperature. Solid-state stability was assessed by subjecting various CD complexes of ziprasidone, spray-dried dispersion (SDD), partially crystalline ziprasidone-SBEßCD salts, and the physical mixture of ziprasidone-SBEßCD to γ-irradiation. Degradant I was formed by oxidation of ziprasidone, which upon aldol condensation with ziprasidone formed degradant II in both solution and solid states. In the solution state, CD complexes with electron-donating side chains, such as SBEßCD and CEßCD, produced the highest oxidative degradation followed by HPßCD with 6, 3, and 4 degrees of substitution. In the solid state, crystalline drug substance and physical mixture of crystalline drug-SBEßCD showed very little to no degradation. In contrast, amorphous ßCD, MßCD, CEßCD, and SBEßCD complexes as well as the amorphous SDD exhibited greatest extent of oxidative degradation. Results suggest that electron-donating side chains of the derivatized CD interact with transition state of the oxidation reaction and catalyze drug degradation in solution, However, higher mobility in the amorphous state of CD-drug complexes promoted chemical instability of ziprasidone under accelerated conditions irrespective of the chemical nature of the side chain on CD.

Influence of dosage form on the intravitreal pharmacokinetics of diclofenac.

PURPOSE: To prepare a suspension form of diclofenac and compare the influence of the injected form (suspension versus solution) on the intravitreal pharmacokinetics of diclofenac in Dutch belted pigmented rabbits. METHODS: Diclofenac acid was prepared and characterized in a suspension formulation. Rabbit eyes were injected with either diclofenac sodium solution (0.3 mg) or diclofenac acid suspension (10 mg) prepared in 0.1 mL balanced salt solution. Rabbits were killed at regular time intervals, the eyes enucleated, and drug content quantified in the vitreous humor and retina-choroid tissue by high-performance liquid chromatography. Pharmacokinetic models were developed for both the dosage forms, and simulations were performed for different doses. RESULTS: Diclofenac acid with an approximate 5-mum particle size exhibited 3.5-fold lower solubility in vitreous humor, when compared with its sodium salt. The estimated settling velocity of the suspension in the vitreous humor was 3 cm/h. After diclofenac sodium salt solution injection, drug levels declined rapidly with no drug levels detectable after 24 hours in the vitreous humor and 4 hours in the RC. Throughout the assessed time course, drug levels were higher in the vitreous. However, sustained, high drug levels were observed in both the vitreous humor and the retina-choroid even on day 21 after diclofenac acid suspension injection, with retina-choroid drug levels being higher beginning at 0.25 hour. The elimination half-life of diclofenac suspension was 24 and 18 days in vitreous and retina-choroid, respectively, compared to 2.9 and 0.9 hours observed with diclofenac sodium. The pharmacokinetic models developed indicated a slow-release distribution or depot compartment for the diclofenac acid suspension in the posterior segment. Simulations indicated the inability of a 10-mg dose of diclofenac sodium solution to sustain drug levels in the vitreous beyond 11 days. CONCLUSIONS: By choosing a less soluble form of a drug such as diclofenac acid, vitreous elimination half-life can be prolonged up to 24 days, potentially resulting in therapeutic levels in the posterior segment tissues for a few months. Higher detectable drug levels in the retina-choroid suggest rapid settling and persistent retention of suspension in retina-choroid tissue.

Local delivery of vancomycin for the prophylaxis of prosthetic device-related infections.

PURPOSE: To evaluate the in vivo efficacy and pharmacokinetics of vancomycin delivered from glycerylmonostearate (GMS) implants in a prosthetic-device based biofilm infection model. METHODS: A biofilm infection model was developed in male Sprague-Dawley rats by implanting a vascular graft on the dorsal side of each rat and infecting it with 1.5 x 10(8) cfu/ml Staphylococcus epidermidis. The rats were divided into 3 groups of 6 rats each: 1) the control group that received no antibiotics, 2) the IM group that received multiple IM injections of vancomycin at a dose of 25 mg/kg every 6 h for a total of 12 doses, and 3) the implant group that received GMS implants designed to deliver vancomycin at a total dose of 300 mg/kg for a period of 4 days. The pharmacokinetics of vancomycin was determined from IM and implant groups by analyzing for vancomycin in blood using HPLC. In vivo efficacy was studied by evaluation of the wound site and the prosthetic device upon excision, for evidence of infection in the form of purulent discharge at the wound site and yellowish discoloration of the prosthetic device and inflammation as sign of biofilm formation. Microbiological evaluation on the wound site and the prosthetic device was performed by culturing the swabs at the wound site and the prosthetic device in sterile tryptic soy broth for 36-48 h at 37 degrees C. RESULTS: Vancomycin was successfully delivered in a sustained manner for 100 h from GMS implants and the resulting plasma profile showed that the concentrations, after an initial burst, plateaued at about of 4.77 +/- 1.43 mug/ml with less fluctuations than the IM group in which the plasma concentrations fluctuated between 2.73 +/- 0.94 mug/ml and 19.26 +/- 3.67 mug/ml. Upon excision of the wound site, all the animals in the control group developed infection in the form of purulent discharge and yellowish discoloration of the prosthetic device. However, none of the rats in the implant group showed evidence of infection clearly demonstrating the efficacy of the local delivery system in preventing infection. Systemically delivered vancomycin by IM injections failed to prevent infection in four out of six rats. Microbiological evaluation of the wound site and prosthetic device resulted in isolation of biofilm-producing organisms such as Staphylococcus epidermidis, Enterococcus faecalis, and Staphylococcus aureus. These organisms were isolated in greater number of animals in the control group compared to the IM and implant groups. CONCLUSIONS: The GMS implants as a delivery system for vancomycin were successful in preventing infection in all the animals compared to the IM and control groups demonstrating the efficacy of a local delivery system in a prosthetic device related biofilm infection model.

Hydrolysis in pharmaceutical formulations.

This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.