Liquid dosage forms

Studying the influence of pH on degradation rate is not as simple as might at first be imagined. If the hydrolysis rate of the dmg in a series of solutions buffered to the required pH is measured and the hydrolytic rate constant is then plotted as a function of pH, a pH-rate profile will be produced, but this will almost certainly be influenced by the buffers used to 

In this equation, is the experimentally determined hydrolytic rate constant, /Cq h the uncatalysed or solvent catalysed rate constant, and /CgH- te the specific acid- and base-catalysis rate constants respectively, ttd ky - are the general acid- and base-catalysis rate constants respectively, and [HX] and [X ] denote the concentrations of protonated and unprotonated forms of the buffer. 

For a complete evaluation of the stability of the dmg, we need to evaluate the catalytic coefficients for specific acid and base catalysis and also to determine the catalytic coefficients of possible buffers which we might wish to use in the formulation. 

First we will examine how to achieve a buffer-independent pH-rate profile, since this will show us at which pH the stability is greatest. By way of illustration we can consider a specific example of a stability study which has been reported for the antihypertensive vasodilator ciclosidomine. Experiments carried out at constant temperature and constant ionic strength using a series of different buffers over the pH range 3-6 produced the graphs shown in Fig. 4.8. These plots show that an increase of buffer concentration, particularly at pH 3, had a marked effect on the hydrolysis rate. The effect of the phosphate buffer on this system became less pronounced with increase of pH and was found to have a negligible effect above pH 7.5. 

Hgure 4.8 Effect of buffer concentration on the hydrolytic rate constant for ciclosidomine at 60°C as a function of pH. 

---

Liquid Dosage Forms. Simple aqueous solutions, symps, elixirs, and tinctures are prepared by dissolution of solutes in the appropriate solvent systems. Adjunct formulation ingredients include certified dyes, flavors, sweeteners, and antimicrobial preservatives. These solutions are filtered under pressure, often using selected filtering aid materials. The products are stored in large tanks, ready for filling into containers. QuaUty control analysis is then performed. 

If a liquid dosage form of a medication exists, it would seem rational to use this dosage form for administration through a feeding tube. Although such a decision may decrease the potential for tube clogging, it may in some instances decrease tolerability of the medication administration. Sorbitol is an excipient found in many liquid medications in amounts sufficient to cause diarrhea. If diarrhea secondary to sorbitol in a liquid medication is suspected in a patient on EN, contact with the manufacturer to ascertain sorbitol content may be necessary. 

As mentioned earlier in this chapter, penicillins are very unstable in aqueous solution by virtue of hydrolysis of the p-lactam ring. A successful method of stabilizing penicillins in liquid dosage forms is to prepare their insoluble salts and formulate them in suspensions. The reduced solubility of the drug in a suspension decreases the amount of drug available for hydrolysis. An example of improved stability of a... 

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. 

The development pharmaceutics discussion for liquid and semi-liquid dosage forms may need to pay particular attention to the following points or issues as well as the general points listed above. 

Sorbitol is a polyhydric alcohol, with a high caloric content. In a survey of 129 oral liquid dosage forms stocked at a large university teaching hospital, 42% contained sorbitol [66]. The sorbitol concentration in the identified products varied from 3.5 to 72% w/v (0.175-3.6 g/mL). 

Both solid and liquid dosage forms may contain saccharin. Saccharin is a nonnutritive sweetening agent, which is 300 times as sweet as sucrose. In a survey of sweetener content of pediatric medications, seven out of nine chewable tablets contained saccharin (0.45-8.0 mg/tablet) and sucrose or mannitol. Seventy-four of the 150 liquid preparations investigated contained saccharin (1.25-33 mg/5 mL) [62], Saccharin is a sulfanamide derivative that should be avoided in children with sulfa allergies [54],... 

Extemporaneous production of pediatric dosage forms is commonly undertaken in hospitals. Without the sophisticated formulation capabilities of pharmaceutical manufacturers, alcohol-based vehicles have been recommended for extemporaneous preparation of liquid dosage forms [73]. There is a critical need to conduct research studies to assist the pharmacist in replacing current formulations with stable, alcohol-free preparations [74]. 

Oral Administration. Oral administration is the preferred route of administration. There is a general consensus among pediatricians and parents that children younger that 5 years of age have great difficulty with, or are unable to swallow, a solid oral dosage form. Manufacturers, therefore, have developed liquid formulations for many of the commonly used pediatric products. The liquid dosage form, however, is not free of problems. Liquid products are often unstable and have short expiration dates accurate measurement and administration of the prescribed dose is also a problem, especially in infants. 

Numerous reports concerning the stability of neomycin in various dosage forms have been published. Simone and Popino298 studied the stability of neomycin in liquid dosage forms such as nasal drops, mouth washes and tinctures. The antibiotic was stable in all the formulations tested, except Dobells solution (a mouth wash), for at least 6 months at 20°C. Some formulations were stable for considerably longer. 

The present chapter deals with calculations involving oral liquid dosage forms including homogenous systems such as syrups and elixirs, and heterogenous systems such as suspensions. 

The majority of streptococcal infections occurred in children under ten, so the new drug proved a particular blessing to the very young (20). The big tablets of sulfanilamide could be administered successfully in hospitals to all but the smallest babies. Most sick children, however, received treatment at home, and mothers found it difficult to get them to swallow large pills. This circumstance seemed to call for a liquid dosage form. A number of attempts to find a suitable vehicle, however, proved unavailing. 

The provision of clear liquid dosage forms of substances (such as S5n"ups, solutions)... 

The dosage form is broadly divided into solid dosage form, liquid dosage form and inhalations which are used both internally as well as externally. 

Liquid dosage forms which are disperse systems (colloidal, i.e., microspheres, nanoparticles, and micelles suspensions and emulsions) often contain preservatives which are methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid in various combinations. A typical example is the antacid suspensions which have high pH values which make the esters of the preservatives susceptible to hydrolysis. One way to circumvent this problem is to use several preservatives in combination with the hope that some quantities of the preservatives will remain to prevent the suspension from microbial attack. A report showing the assay of the four esters and the parent acid (one of the decomposition products) in drug products in which all the preservatives were used has been given [13]. 

Liquid Dosage Forms Sodium nitropruside in aqueous solution for injection will remain stable for up to one year if protected from light however, its shelf life is about 4h when exposed to normal room light [35]. It has been reported that uric acid increases the photostability of sulfathiazole sodium in solutions [36]. Further dZ-methionine increased the photostability of ascorbic acid in solution [37]. The... 

---