Liquid and Semisolid Formulation Considerations on Manufacturability

Aug 31, 2023

By David Johnston, President, Oread Corporation

The formulation and manufacturability of pharmaceutical solutions and semisolids involves a combination of sound knowledge in basic chemistry and "hands-on" experience at both the laboratory bench and pilot plant scale. The various dosage forms have their own advantages and disadvantages considering the physicochemical properties of the active pharmaceutical ingredient (solubility, stability, etc.) as well as the route of product administration and intended population. Thus, it is important for the formulation scientist and the manufacturing technical personnel to work closely together as new products are developed and brought to market.

Liquid and semisolid products for therapeutic use include solutions, suspensions, and emulsions. In solutions, the active drug is dissolved in a suitable pharmaceutical solvent and delivered as a solution, spray, or solid. Solutions have many therapeutic uses and can be delivered both orally and topically. The same is true for suspensions, where the drug is suspended in a suitable medium. Both liquid and semisolid suspensions are used today. For both of these dosage forms, the formulations will differ significantly when intended for topical vs. oral delivery.

While both types of products may contain solubilizing agents, suspending agents, and preservatives, they also may contain unique ingredients, such as flavors and perfumes, depending on the final use. The third type of product, emulsions, consists of two phases (water and oil), and has the active drug dissolved or suspended in one of the phases. Emulsions can range in viscosity from thin lotions to solid creams. Again, formulation ingredients may change depending on intended use and the phase in which the drug is dispersed or dissolved.

The selection of the appropriate formulation for each individual product is based on several factors. These factors can include intended use and method of application in addition to solubility and stability of the drug. For oral products, solution and suspension products are often used in pediatrics or for patients who may experience difficulty in swallowing. Flavoring systems are often quite different for these two groups. A flavor that appeals to a two year old child will not be the same as that palatable to a geriatric patient. In topical emulsion products, the viscosity of the final product may be determined by the intended use: a product for wide spread body use may have a much lower viscosity than one intended for spot use. Each dosage form has advantages and disadvantages for both the patient population and the long term stability of the drug.

Topical preparations can often have quite complicated formulations, and this can lead to multiple issues in manufacturing and packaging. Solutions are usually fairly easy to manufacture and package. If the drug is readily soluble in water, a simple solution may be manufactured. Often, however, if the product is for oral use, flavors and colors are added. Since most flavors and many colors are not water soluble, the use of solubilizing agents or specially prepared dispersible flavors and colors may be used. In all preparations containing water, prevention of microbial contamination must be considered. If the product contains large enough amounts of alcohol or sugar, there may not be a need for additional preservatives.

But most aqueous products do require preservation, and the careful selection of the proper preservative is important. Packaging of solutions is fairly simple if they are put into glass bottles. But filling into plastic bottles raises issues of container and closure compatibility as well as the selection of the best label and glue systems to prevent migration through the plastic bottle into the product. Many solutions are also used for specialized applications, and these often require unique containers. Nasal sprays, for example, can be filled into bottles with a spray pump packaged separately or where the spray pump is actually placed in the bottle at time of filling. Specialized pieces of filling equipment are used for pump-in-place packages.

Suspensions, including simple ointments, are more difficult to manufacture and package due to the drug's natural tendency to drop out of suspension. Typically, a drug is suspended in a suitable solvent (usually water) with the aid of a suspending agent. If a suspending agent is not used, the result is what is called a "shake lotion," i.e. something that must be shaken vigorously by the patient before use in order to re-suspend the drug or active agent.

Suspending agents are used to prevent the settling of the drug during storage and negate the need to shake and re-suspend the drug before each use. The correct suspending agent will be chosen based on compatibility with the drug and solvent system. The correct amount of agent must be used to ensure the product is the correct viscosity to keep the drug in suspension but prevent solid caking. During manufacture of suspensions, care must be taken to get the drug suspended properly without the incorporation of excess air, which can affect not only the viscosity of the finished product but also the dispensing of the correct amount of drug if the dosing is by physical measurement (i.e. by the spoonful). If heat is used during the manufacture, care must be taken during the cool-down of the product to prevent settling.

Filling of suspension products can also be difficult. Usually the liquid preparation must be carefully agitated during the entire filling process to ensure that the proper amount of drug goes into each bottle. Content uniformity per bottle and dose of suspension products can often be difficult to maintain without the proper mixing and filling equipment in the manufacturing area. Simple ointments can also be described as solid suspensions. For simple ointments, the drug is suspended in a heated petrolatum base and then slowly cooled and mixed until it forms a homogeneous mass. Aspects involved in cooling and packaging are the same as for emulsions as mentioned below.

Emulsion products typically consist of two distinct phases. During manufacturing, each phase is manufactured separately, and then the two phases are combined so that globules of the internal discontinuous phase are dispersed evenly in the external continuous phase. Typically, each phase is heated. The oil phase is heated to either melt or mix the ingredients. The aqueous phase is also heated to match the oil phase. The drug is dissolved or dispersed in one of the phases depending on its solubility and stability. At a certain temperature, the two phases are mixed to form an emulsion. The emulsion is then typically cooled down slowly to room temperature.

Several different vessels are employed during manufacturing. The two phases may be separately heated in simple jacketed vessels. The drug is usually dissolved in a small amount of solvent or water with an added dispersing agent and then added to one of the phases. For forming the emulsion, typically one of the heated phases is placed in a mixer with different types of mixing devices. Oftentimes, a homogenizing mixer is built into the tank. This is used while the second phase is added to the first phase and the two phases are forced together through the small opening in the homogenizing head to form the correct globule size emulsion. The physical stability of the emulsion is quite often dependent on a certain globule size of the dispersed phase, and this can be controlled by varying the homogenizing mixer parameters.

After the formation of the primary emulsion, the homogenizing head is disengaged, and paddle or gate mixers are used in combination with scraping blades while the product is cooled down. Since the primary emulsion is often formed while the two phases are very hot, cooling agents are used in the walls of the jacketed tanks to lower the temperature of the emulsion and force congealing. Since the fastest cooling occurs at the walls of the vessel that contain the cooling liquids, congealing occurs first there. The scraper blades scrape the solidified emulsion off the walls and allow more liquid emulsion to contact the wall and thus cool faster. The paddle blades maintain homogeneity in the product by continuously moving the whole mass during the cool-down process. Care must be taken during the final cool-down to prevent extreme aeration. If too much air is incorporated during the cool-down process, the physical volume of the product will increase, and this can adversely affect the correct filling of the product into containers.

After complete cool-down of the product, it is usually transferred by pumping to storage tanks, which can be transported and connected to filling lines. Again, care must be taken during the pumping process not to introduce air into the product. Also, shear must be avoided as it might break the emulsion or change the viscosity or other physical characteristics of the product. Emulsion products are typically filled by weight into bottles or tubes. Filling is done by weight or volume, and an over-aerated product will have too much volume to fit the correct amount into the container.

Many specialized pieces of equipment can be used in the manufacture of emulsions to protect the drug's physical or chemical characteristics. These can include specialized blenders to disperse the drug in the various phases at a predetermined rate (homogenizing mixers, colloid mills, and simple mixers) and rapid heat exchangers to shock cool products and enhance viscosity and droplet size distribution as well as other parameters.

From the above, it can be seen that the formulation of liquid and semisolid products can be quite varied and will depend on the characteristics of the drug as well as the ultimate use and population for the product. In turn, the selected formulation will have major effects on the manufacturability of the product. In addition, the actual manufacturing and packaging of these types of products often require specialized equipment and techniques.

For more information: David Johnston, President, Oread, 1501 Wakarusa Dr., Lawrence, KS 66047-1803. Tel: 785-749-0034. Fax: 785-749-1882.

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