Large-volume dosage forms

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

When attempting to convert a manual method into an automated method, there are certain elements, such as tablet size and solvent selection, which will have an impact on the ease of the conversion from manual to automated. For instance, some of the elements of an assay method that would make it easier to automate would be that the dosage form fits into a test tube the extraction uses neutral media or acid not more concentrated than 0.1 M makes use of nonvolatile, low-toxicity solvents does not use surfactants and uses premixed, room-temperature solvents. Some of the elements of a dissolution method that would make it easier to automate would be that the dosage form fits in the sample carousel, does not use media more concentrated than 0.1 M acid, does not use isopropanol or surfactant in large quantities, uses magnetic sinkers or no sinkers at all, and uses no or minimal reagent addition volumes for pH control. 

In the case of low-dose drug products, content uniformity of the dosage form can be negatively affected if the particle size of the API is either too large or the size distribution is too broad. This could result in the need to deliver API below a certain size to ensure content uniformity. Recently, Rohr et al.4 expanded upon previous work to develop a statistical model predicting the volume mean diameter of API necessary to meet USP stage 1 criteria on content uniformity for tablets with a 99% confidence level [Eq. (8.1)] ... 

As discussed earlier, the pH of the rectal fluid can have a marked effect on the absorption of drugs from the rectum. Since the rectal fluid has a relatively low buffering capacity and the volume of the rectal fluid is small, it might be expected that the contents of the rectal dosage form largely control the pH of the rectum during administration. On this basis, one may be able to utilize the pH characteristics of the drug and incorporate suitable buffers and other excipients in the... 

There are at least theoretical solutions to these two problems. The large volume is less of a problem in dosage forms such as instant or effervescent granules of ibuprofen [505], while the use of large quantities of solvents can sometimes be avoided by using a solvent-free production process such as the roll-mixing process for triturations. 

To overcome insufficient stability in liquid state, dispersible tablets and effervescent dosage forms provide a dry alternative to liquid but are not without inherent issues (large volume of diluent, bicarbonate ingestion, sodium and/or potassium content not suitable for renally impaired patients, difficult taste masking). 

As mentioned above, veterinary dosage forms can be very large and packaging of multiple doses achieved through the use of large packages. This presents substantial demands upon stability test chambers due to the sheer volume of product that must be stored. Appropriate sampling-size protocols can aid in the solution of this issue. 

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