Excipient formulations

Table 3.5 Comparison of M0 for three proteins without and with two excipients, formulated each with 50% w/w of the protein (part of Tables 1 and 2 from [3.72)]...

The range of complexity of solubilized oral formulations filled into a capsule varies from a simple one-excipient formulation such as PEG 400 or a long-chain triglyceride, to complex microemulsion preconcentrates which contain oil, cosolvent, and surfactant excipients. The preferred water-soluble organic solvents... 

As a guide to solubilized oral formulation drug development, the following examples illustrate the formulation philosophy of simple to complex . Starting with one-excipient formulations to complex microemulsion preconcentrates. 

The optical microscope is a valuable tool in the laboratory and has numerous applications in most industries. Depending on the type of data that is required to solve a particular problem, optical microscopy can provide information on particle size, particle morphology, color, appearance, birefringence, etc. There are many accessories and techniques for optical microscopy that may be employed for the characterization of the physical properties of materials and the identification of unknowns, etc. Utilization of a hot-stage accessory on the microscope for the characterization of materials, including pharmaceutical solids (drug substances, excipients, formulations, etc.), can be extremely valuable. As with any instrument, there are many experimental conditions and techniques for the hot-stage microscope that may be used to collect different types of data. Often, various microscope objectives, optical filters, ramp rates, immersion media, sample preparation techniques, microchemical tests, fusion methods, etc., can be utilized. 

PVAc is an inexpensive, high-tonnage bulk commodity polymer which, unlike most vinyl polymers, is moderately biodegradable and has been used in pharmaceutical excipient formulations. PVAc has also been shown to exhibit... 

Vibrational spectroscopy is especially appropriate to investigate this type of system, since it allows the detection and characterization of both intra- and intermolecular interactions. It does not require any special sample preparation, thus avoiding mechanical influences which may alter the physicochemical properties of the drug-excipient formulation. Inelastic Neutron Scattering (INS), in particular, is quite suitable for the study of these kinds of interactions involving hydrogen atoms. 

CP-MAS NMR spectra are influenced by the local environment of the observed nucleus rather than by the long-range molecular order, and useful information can be extracted from the spectra of pharmaceutical compounds whether they are powdered microcrystals or amorphous preparations. Unlike diffraction techniques, for example, CP-MAS NMR can access information on local dynamics with appropriate relaxation measurements and line shape analyses. Moreover, with appropriate calibration, it is possible to gain quantitative information from heterogeneous samples, such as drug-excipient formulations and co-crystals. A comprehensive description of CP-MAS NMR methods and their applications to small organic molecules is beyond the scope of this chapter, and the reader is referred to several excellent reviews for more extensive perspectives in this regard. 

Perhaps a more specialized case of using plasticizers in acrylic formulations can be found in drug delivery patches. Here, plasticizing additives called excipients... 

The second example is the SE-HPLC analysis of recombinant hGH. In this example, SE-HPLC is used for both a purity and a protein concentration method for bulk and formulated finished products. This method selectively separates both low molecular weight excipient materials and high molecular weight dimer and aggregate forms of hGH from monomeric hGH, as shown... 

Table 3.3 Common excipients used in the formulation of drug products.

Characterisation Typical data that may be provided to describe the physical and chemical characteristics of the drug substance are shown in Figure 6.3. The description of the drug product should include the recipe detailing all the other ingredients (excipients) that are used to formulate the final product. It is vital to provide adequate data on the dissolution behaviour of the drug product, as the reviewer may wish to tie this in with pharmacokinetic or bioavailability data submitted in the other modules. 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

Figure 4.50. Cumulative dissolution results. Two experimental tablet formulations were tested against each other in a dissolution test in which tablets are immersed in a stirred aqueous medium (number of tablets, constructional details and operation of apparatus, and amount of medium are givens). Eighty or more percent of the drug in either formulation is set free within 10 minutes. The slow terminal release displayed by formulation B could point towards an unwanted drug/excipient interaction. The vertical bars indicate ymean - with Sy 3%. A simple linear/exponential model was used to approximate the data for the strength 2 formulation. Strengths I and 3 are not depicted but look very similar.

Figure 4.52. Coefficients of variation that reflect both tablet to tablet and analytical variability. For formulation B, particularly strengths 2 and 3, the drop in CV with higher cumulative release (a - b) is marked, cf. Fig, 4.50. When the dissolution rate is high, individual differences dominate, while towards the end analytical uncertainty is all that remains. The very low CVs obtained with strength 3 of formulation A ( 0.7-0.8%, data offset by +10% for clarity) are indicative of the analytical uncertainty. Because content uniformity is harder to achieve the lower the drug-to-excipient ratio, this pattern is not unexpected.

Occasionally in the synthesis of the copolymers, insoluble material is produced. This results from polymer containing blocks of polyglycolide rather than the desired random structure. Obviously, such compositions would have considerable effect on the performance of controlled release formulations utilizing those polymers. This problem is particularly evident when one is seeking to utilize the 50 50 glycolide/lactide copolymer as a biodegradable excipient. However, with carefully controlled polymerization conditions, useful 50 50 polymer is readily produced. 

The process of formulation for any of the above is generically the same, beginning with some form of product specification and ending with one or more formulations that meet the requirements. Correct choice of additives or excipients is paramount in the provision of efficacy, stability, and safety. For instance, the excipients may be chemically or physically incompatible with the drug or they may exhibit batchwise variability to such an extent that at the extremes of their specification they may cause failure in achieving the desired drug release profile. In addition, some excipients, especially those that are hydroscopic, may be contraindicated if the formulation is to be manufactured in tropical countries. Flence formulators must work in a design space that is multidimensional in nature and virtually impossible to conceptualize. 

The Cadila system [13] has been designed to formulate tablets for drugs based on their physical (solubility, hydroscopicity, etc), chemical (functional groups), and biologically interrelated (dissolution rate) properties. The system first identifies the desirable properties for optimum compatibility with the drug, selects those excipients that have the required properties, and then recommends proportions based on the assumption that all tablet formulations comprise at least one binder, one disintegrant, and one lubricant. Other... 

The portal of drug entry The physical form of the drug product The design and formulation of the product The method of manufacture of the drug product Various physicochemical properties of the drug and excipients... 

It should again be emphasized that at the onset of a new drug program, there are only small amounts of drug substance at hand. One of the first tasks for the preformulation scientist is to establish the framework within which the first clinical batches can be formulated. To this end it is important to know with which common excipients the drug is compatible. Below, the distinction will be made between solid and liquid dosage forms. 

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