Formulation and Product Development

Formulation and Product Development
by D. Papadimitriou

Human disease and man's instinct to survive has led to the discovery of medicine. Itsuse by means of crude preparation dates long before recorded history. The instinct ofprimitive man to relieve wound pain by bathing the wound in cool water or wrapping it witha fresh leaf or mud is generated from the possibility of belief. Through trial and error,primitive man learned which therapies were more effective. From these beginnings thepractice of product formulation began.

Initial formulation success can be attributed to the appropriate medicine, effectivepreparation and placebo effects. Early successful experiences cited formulations forprescriptions that used formulative vehicles such as wine, beer, honey and milk to preparevarious medicines. Equipment included mortars, mills, sieves and scales. Early Egyptiansused such equipment and compounds to formulate pills, suppositories, inhalants, lotions,plasters and enemas.

Throughout history, many individuals contributed to the advancement of healthpreparations. For example, Galen, a Greek pharmacist-physician, revolutionized thedevelopment of medicinal compounding. The refinement of medicinal preparations andemphasis on elegant composition is a contribution of Arabian pharmacists who developed thepleasant flavored preparations for syrups and elixirs.

Current pharmaceutical and food supplement preparations are identified as "dosageforms." This term is descriptive and defines a preparation that can be produced todeliver medications in measured and prescribed amounts. Some procedures required forachieving this objective can be elaborate--for example, the manufacturing of tablets.Tablets are an example of product elegance offering distinct advantages over other dosageforms. Its production requires a broad scientific understanding of powder properties andhandling, compaction characteristics, homogeneity of blending, compatibility concerns andbioavailability. Such requirements are fulfilled with appreciable bench experience and anunderstanding in solid chemistry, physics, mathematics, pharmacokinetics and materialscience.

Official publications from USP/NF, German Commission E and herbal monographs for theAmerican Botanical Council describe detailed specifications of active components, drugsand herbs to qualify them for formulating products. Specifically, test procedures aredefined to assure quality by ensuring uniformity of content and performance. However,these publications do not define the procedures by which dosage forms are to be prepared.Decisions for equipment, manufacturing, product integrity and packaging are left to thediscretion of the formulator. The main task of a formulator is to produce a product thatis elegant, stable and functional. Therefore, to define the formulation of a productrequires the combination of knowledge from a variety of scientific fields with the aim toproduce a product that is functional, affordable and consumer-friendly.

Product dosage forms fall in three basic categories: solids, liquids and semi-solids.Solids include tablets, capsules, powders and bars. Liquids include solutions, emulsions,colloids and suspensions. Semi-solids include ointments, lotions, creams, pastes, gels andsuppositories. Each class of dosage forms imposes specific challenges on the formulator.For tablets, the powder blend to be compressed should be free-flowing without excess offine particles, non-segregating, sufficiently dense, non-hygroscopic, compressible andadequately lubricated. The formulator uses various tests to monitor the quality (integrityand composition) of manufactured tablets. These measurements include weighing, friability,thickness, disintegration times and dissolution times. Often changes become noticeableafter production. In some instances, tablets become increasingly harder over time due tohygroscopic materials or to incompatibilities between constituents or even to ingredientswith a low melting point. When melted, due to high temperature exposure, the product mayre-solidify and glue the tablet together preventing its disintegration. In otherinstances, photosensitive materials may discolor tablets.

Liquids generate new challenges since chemical reactions from degradation orincompatibilities occur much faster in a liquid state. A frequent problem with liquidformulations is sedimentation or crystallization of constituents. This effect destroys thehomogeneity of the product and can occur over time as the product is exposed to variousstorage temperatures. While the formulator attempts to resolve such problems, there is aconcern that corrective actions may impact taste and subsequent acceptability of theproduct by the consumer.

Heterogeneous systems (multi-phase) such as semisolids, colloids and emulsions imposeadditional concerns to the formulator. These systems are thermodynamically unstable andhave the tendency to separate into individual phases. Suspensions and colloids represent asolid-liquid two-phase system while emulsions represent a liquid-liquid two-phase system.Suspensions tend to settle forming a cake that is hard and does not disperse easily. Bymeans of surfactants, soluble polymers and electrolytes, the formulator can prevent theparticle from settling and create a suspension that either resists sedimentation orloosens sediment so it can easily be dispersed once shaken. Emulsions can be usedinternally either by mouth or by injection. However, a good majority is available to theconsumer primarily for topical use such as lotions and creams. These preparations maysuffer from phase separation problems. The oil phase in the form of globules containsfatty alcohol, silica and other lipid soluble components that coalesce and separate fromthe water phase that contains preservatives, humectants, gelling agents and co-solvents.It is a challenge for the formulator to identify the surfactant system and themanufacturing procedures that will keep the oil and water phases mixed.

Once a product is consumed, its constituents will either be absorbed or excreted. Ifabsorbed, the active principles circulating in the blood are metabolized by the liver anddistributed to various tissues and are eventually excreted either intact or asmetabolites. For single component dosage forms, as with most drug products, it is possibleto follow the course of active principles in the body. The study of the physical/chemicalproperties of a drug in relation to its absorption-distribution-elimination in the humanbody is called biopharmaceutics and is a pivotal activity to the final formulation of apharmaceutical product. As the food supplement industry moves to greater sophistication,it becomes implicit that product formulation cannot be considered isolated from the humanbody. Feedback between formulation and product efficacy is needed. Economic constraints,the presence of numerous active principles acting synergistically toward product efficacyor the presence of unidentified active principles make the the drug industry difficult tofollow. In this instance, clinical outcome studies and positive feedback often determineproduct efficacy.

Dimitri Papadimitriou, Ph.D. is with Arevno Consultants. He may be contacted at [email protected].