Excipients

In order to achieve appropriate levels of solubilization, dissolution rate and potentially supersaturation, excipients are required (Rowe et al., 2006 International Pharmaceutical Excipients Council 2006). Excipients are components of dosage forms which are included for a variety of reasons and are usually not directly associated with the pharmacological activity of the selected drug substance. Historically, excipients have comprised ingredients e.g., to mask or improve taste, to optimize...

Propylene Glycol Pharmacologic Classification

Predicted DCS classification of Itraconazole (A) as well as the effect of solubility on fraction absorbed (B). The Spider plot suggest good oral bioavailability at solubility values above 100 pg mL. The solubility of itraconazole at neutral pH is estimated at 1 ng mL. Itraconazole can be solubilized in 2-hydroxypropyl-p-cyclodextrin to levels in excess of 10 mg mL which suggests Class I behavior (C). (See color insert after Index.)

Design of Permeability Screening Experiments

From the different examples reviewed, it is clear that when performing absorption studies, the experimental conditions will have a major impact on the generated data. The design of experimental conditions for PAMPA assays in early screening can probably be considered as straightforward. The biorelevant DS-PAMPA model may certainly be a good option for first screening experiments addressing passive transcellular absorption. The use of other physicochemical methods, such as calculation of...

Inclusion Complexes

Application of cosolvents and surfactants may often not achieve the required solubility enhancement, or ratio between the desired dose and the intrinsic solubility of the pharmaceutical agent. If the desired solubility enhancement is too high, then dispersed systems (e.g., suspensions, emulsions) may be the only option. Cyclodextrins may offer an alternative route. The only cyclodextrins that are generally recognized for use in injectable products are 2-hydropropyl-beta-cyclodextrin (HP-BCD)...

Correlation

Although it is the ultimate goal to predict in vivo formulation behavior based on in vitro dissolution testing using biorelevant media, the number of studies in which in vitro-in vivo correlations (IVIVC) have been described, is limited. Finding a correlation between in vitro dissolution testing and in vivo performance will be challenging due to the multiple factors which affect the blood concentration-time profile. Using a mathematical simulation model based on the Noyes-Whitney equation,...

Solvents Not Widely Used for Topical Preparations

While the above describes some of the more commonly used solvents for topical formulations, and emphasises those that appear in the FDA inactive ingredient guide (1996), the listing does not describe some of the solvents that are widely used in research studies of topical delivery. Dimethylsulphoxide (DMSO) and similar solvents such as dimethylacetamide (DMA) and dimethylformamide (DMF) are popular in these studies, but present problems. All three of these solvents penetrate well into human...

References

Aspects of Biocatalyst Stability in Organic Solvents. Biocatalysis 1987 1 99-108. Affleck R, Xu ZF, Suzawa V, Focht K, Clark DS, and Dordick JS. Enzymatic Catalysis and Dynamics in Low-water Environments. Proc Natl Acad Sci USA 1992 89 1100-1104. Alexandrescu AT, Ng YL, and Dobson CM. Characterization of a Trifluo-roethanol Induced Partially Folded State of a-lactalbumin. J Mol Biol 1994 235 587-599. Almarsson O and Klibanov AM. Remarkable Activation of Enzymes in...

Interplay Between Thermodynamics Kinetics and Molecular Recognition

When a compound exists in various solid-state forms there are two important questions to address (1) what is their relative thermodynamic stability, or the conditions and direction in which a transformation can occur, and (2) how long will it take for the transformation to reach equilibrium Thermodynamics provides information about the first question and kinetics about the second. While thermodynamics establishes the stability domains of the various solid states, once a metastable domain is...

Water Insoluble Organic Solvents and Solids

A lipid-based oral formulation is used for water-insoluble drugs in cases where typical formulation approaches (i.e., solid wet granulation, solid dry granulation, water-soluble liquid in a capsule) do not provide the required bioavail-ability, or when the drug itself is an oily substance (e.g., dronabinol, ethyl icosapentate, indomethacin farnesil, teprenone, and tocopherol nicotinate). The water-insoluble solvents used in commercially available solubilized oral formulations include oleic...

Methods for Measuring Protein Solubility

While the solubility of most small molecules can be determined by dissolving the solid bulk in volatile solvents, drying, and dissolving in various solutions until no further dissolution is observed, it is risky to expose protein solids to volatile solvents without protein denaturation or to generate pure protein solids in their native conformation that lack other excipients. Thus, protein solubility is generally determined by concentrating the protein solution until a phase change...

Brief History From CFCs to HFAs

The first metered dose inhaler, Medihaler EpiTM was introduced in 1956 by Riker Laboratories (3M Pharmaceuticals) for the management of asthma and COPD. The delivery device has been well accepted since that time, as evidenced by the annual production of over a half-billion units (McDonald and Martin, 2000). Since the introduction of the MDI, p-adrenergic agonists, anticholinergics, corticosteroids, and cromolyn compounds have been the staple of management for the commonly occurring lung...

Diseased Compromised Skin and Solvent Selection

Numerous physiological factors in healthy and diseased skin can affect topical drug delivery and consequently formulation design. For example, neonatal skin is more permeable than adult skin and site to site variations in permeability are well known with genital tissue more permeable than that on the head and neck with arm and leg skin even less permeable. However, it is with compromised skin, found in many conditions where topical dosage forms are applied, where solvent selection can be...

Definition of Protein Solubility

Protein solubility is a thermodynamic characteristic of the protein solvent system defined as the concentration of soluble protein in equilibrium with the solid phase at a given pH, temperature, and solvent composition (Flynn, 1984 Arakawa and Timasheff, 1985 Middaugh and Volkin, 1992). For practical purposes, solubility of proteins can be defined as the maximum amount of protein that remains in a visibly clear solution (i.e. does not show protein precipitates, crystals, gels, or hazy soluble...

Aggregates as Promiscuous False Positive HTS Hits

It has been observed that certain compounds appear as frequent hitters in HTS regardless of the biological target, especially when screened at higher than 10 J.M concentration. Figure 5 shows examples of promiscuous HTS hits McGovern et al., 2002 McGovern et al., 2003 McGovern and Shoichet, 2003 . These spurious hits have low potency at 1-10 J.M, noncompetitive and reversible inhibition, flat SAR and poor selectivity. The potency increases with incubation time, but decreases with higher enzyme...

PH Bile Salts and Proteins for Biorelevance pH Adjustment

The importance of the pH to mimic the physiological conditions has been introduced in the section on Physiological Relevance. It has been demonstrated that media buffered to a pH varying from 5 to 8 were compatible with the Caco-2 cell monolayer Palm et al., 1999 Neuhoff et al., 2003, 2005 . PAMPA models have even been shown to be compatible with a wider range of pH, i.e., from 4 to 10 Bermejo etal., 2004 . Yamashita and coworkers studied the effect of medium pH on the transport rate of several...

Propylene Glycol Diabetic Insulin

Solubility of proteins in co-solvent and non-aqueous conditions. dipole moment. Some success with polar protic solvents and polar aprotic solvents suggested that solubility can be enhanced by dissolution in an organic vehicle with a high dielectric constant Chin et al., 1994 Houen, 1996 . Increasing the dielectric constant may increase solubility, but it may also decrease stability. In general, no single parameter predicted lysozyme solubility, but protic polar solvents and hydrophilic...