Drug Absorption Modeling as a Tool to Define the Strategy in Clinical Formulation Development

The purpose of this mini review is to discuss the use of physiologically-based drug absorption modeling to guide the formulation development. Following an introduction to drug absorption modeling, this article focuses on the preclinical formulation development. Case studies are presented, where the emphasis is not only the prediction of absolute exposure values, but also their change with altered input values. Sensitivity analysis of technologically relevant parameters, like the drug's particle size, dose and solubility, is presented as the basis to define the clinical formulation strategy. Taking the concept even one step further, the article shows how the entire design space for drug absorption can be constructed. This most accurate prediction level is mainly foreseen once clinical data is available and an example is provided using mefenamic acid as a model drug. Physiologically-based modeling is expected to be more often used by formulators in the future. It has the potential to become an indispensable tool to guide the formulation development of challenging drugs, which will help minimize both risks and costs of formulation developmen

Advancing Pharmaceutical Dry Milling by Process Analytics and Robustness Testing

The objectives of this work were to implement on-line dynamic image analysis and to introduce a novel at-line flowability analyzer in pharmaceutical dry milling. We used a pilot-scale conical mill and flowability of a placebo granulate was monitored using a powder avalanching analyzer. Experiments were designed and evaluated by means of response surface methodology in conjunction with robustness testing. The process parameters impeller speed and screen size significantly affected the particle size distribution and flow rate of the milled granules. Feeder speed did not affect the particle size, but displayed a statistically significant influence on the flow responses. Robustness testing was able to capture the effect of noise factors on the responses and showed clear differences between different lots of the placebo granulate in addition to temperature-dependent changes in flow behavior. Thus, on-line dynamic image analysis and at-line flowability characterization, together as complementary process analytical tools, provided valuable information. The combined analysis was of particular interest for testing the process and noise factors so that future process development can profit from this advancement in dry millin

Introduction of a Theoretical Splashing Degree to Assess the Performance of Low-Viscosity Oils in Filling of Capsules

These days an alternative to soft capsules is liquid-filled hard capsules. Their filling technology was investigated earlier with highly viscous formulations, while hardly any academic research focused on low-viscosity systems. Accordingly, this work addressed the filling of such oils that are splashing during the dosing process. It was aimed to first study capsule filling, using middle-chain triglycerides as reference oil, in order to then evaluate the concept of a new theoretical splashing degree for different oils. A laboratory-scale filling machine was used that included capsule sealing. Thus, the liquid encapsulation by microspray technology was employed to seal the dosage form. As a result of the study with reference oil, the filling volume and the temperature were found to be significant for the rate of leaking capsules. The filling volume was also important for weight variability of the capsules. However, most critical for this variability was the diameter of the filling nozzle. We proposed a power law for the coefficient of weight variability as a function of the nozzle diameter and the obtained exponent agreed with the proposed theory. Subsequently, a comparison of different oils revealed that the relative splashing degree shared a correlation with the coefficient of the capsule weight variability (Pearson product moment correlation of r = 0.990). The novel theoretical concept was therefore found to be predictive for weight variability of the filled capsules. Finally, guidance was provided for the process development of liquid-filled capsules using low-viscosity oil

Validity of a Power Law Approach to Model Tablet Strength as a Function of Compaction Pressure

Designing quality into dosage forms should not be only based on qualitative or purely heuristic relations. A knowledge space must be generated, in which at least some mechanistic understanding is included. This is of particular interest for critical dosage form parameters like the strength of tablets. In line with this consideration, the scope of the work is to explore the validity range of a theoretically derived power law for the tensile strength of tablets. Different grades of microcrystalline cellulose and lactose, as well as mixtures thereof, were used to compress model tablets. The power law was found to hold true in a low pressure range, which agreed with theoretical expectation. This low pressure range depended on the individual material characteristics, but as a rule of thumb, the tablets having a porosity of more than about 30% or being compressed below 100MPa were generally well explained by the tensile strength relationship. Tablets at higher densities were less adequately described by the theory that is based on large-scale heterogeneity of the relevant contact points in the compact. Tablets close to the unity density therefore require other theoretical approaches. More research is needed to understand tablet strength in a wider range of compaction pressure

Understanding interactions of oleic acid with basic drugs in solid lipids on different biopharmaceutical levels

Recently, the impact of intestinal supersaturation on absorption of poorly water-soluble drugs has raised much interest among researchers. A focus has been mostly to study excipient effects on maintenance of drug supersaturation. The aim of the present study was to better understand the effects of drug-excipient interactions on the level of the anhydrous formulation, upon dispersion in simple buffer media and, in particular, regarding precipitation kinetics. A solid lipid-based formulation comprising PEG-32 stearate and oleic acid (OA) (8:2 w/w) was developed as a model. Loratadine (pKa = 4.33) and carvedilol (pKa = 8.74) were chosen as basic drugs. UV/FTIR spectroscopy and viscometry were used to characterize drug-OA molecular interactions in solution, while solid formulations were studied using x-ray diffraction, thermal analysis and van’t Hoff solubility-temperature plots. Precipitation kinetics of drug formulations was real-time monitored in phosphate buffer (pH = 6.5) by focused beam reflectance measurements. It was found that the addition of OA in the formulations resulted in substantial drug solubility increase. Although the drug-OA interactions appeared to be partially lost upon formulation dispersion, the extent of precipitation was markedly lowered compared to the formulations without OA. A Precipitation number (Pnc) was introduced as a ratio of a relevant residence time of drug in the gastrointestinal tract (GIT) to the induction time (the onset time of crystalline precipitation). Without OA, Pnc was already taking critical values (>1), while the anhydrous formulation was still below saturation for both model drugs. Interestingly, the addition of OA resulted in amorphous instead of crystalline precipitates, which is advantageous for drug re-dissolution and absorption. In conclusion, this study provides an improved understanding of OA and basic drug interactions on different levels of in vitro performance for more rational oral formulation development

Insights into Drug Precipitation Kinetics during In Vitro Digestion of a Lipid-Based Drug Delivery System Using In-Line Raman Spectroscopy and Mathematical Modeling

ABSTRACT: Purpose: To determine drug precipitation during in vitro lipolysis of a lipid-based drug delivery system (LBDDS) using Raman spectroscopy as a real-time monitoring technique. A second aim was to describe the kinetics of lipolysis-triggered drug precipitation using a theoretical nucleation and growth model. Methods: A model LBDDS containing different concentration of fenofibrate was digested in vitro and drug precipitation was determined after ultracentrifugation and nanofiltration (off-line methods), as well as by Raman spectroscopy (in-line method). Subsequently, a theoretical nucleation and growth model was fitted to the obtained drug crystallization profiles by considering the lipolysis-triggered change in drug solubility. Results: Compared with standard off-line measurements, Raman spectroscopy enabled a more robust and highly time-resolved analysis of lipolysis-triggered drug precipitation. Although the formulation was rapidly digested, fenofibrate remained in a supersaturated state for several minutes before beginning to crystallize. The in vitro digestion results were in excellent agreement with the theoretical model (R 2  > 0.976). Conclusions: The combination of real-time Raman spectroscopy and mathematical modeling provided insights into the kinetics of lipolysis-triggered drug crystallization. This knowledge allows a better biopharmaceutical understanding and will, ultimately, lead to the improved development of lipid-based drug formulation

Supersaturated lipid-based formulations to enhance the oral bioavailability of venetoclax

Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required

A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients

Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink

Purpose: In vitro lipolysis is widely utilized for predicting in vivo performance of oral lipid-based formulations (LBFs). However, evaluation of LBFs in the absence of an absorption sink may have limited in vivo relevance. This study aimed at employing biopharmaceutical modeling to simulate LBF digestion and drug supersaturation in a continuous absorptive environment. Methods: Three fenofibrate-loaded LBFs were characterized in vitro (dispersion and lipolysis) and drug precipitation was monitored using in-line Raman spectroscopy. In vitro data were combined with pharmacokinetic data derived from an in vivo study in pigs to simulate intestinal LBF transit. This biopharmaceutical model allowed calculation of lipolysis-triggered drug supersaturation while drug and lipolysis products are absorbed from the intestine. Results: The biopharmaceutical model predicted that, in a continuous absorption environment, fenofibrate supersaturation was considerably lower compared to in vitro lipolysis (non-sink). Hence, the extensive drug precipitation observed in vitro was predicted to be unlikely in vivo. The absorption of lipolysis products increased drug supersaturation, but drug precipitation was unlikely for highly permeable drugs. Conclusions: Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered

In Silico, in Vitro, and in Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax

The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases