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The Evolution of Dosage Forms

Dosage Forms Dosage Forms

Dosage forms date back to 1500 B.C. in ancient Egypt when primitive man used plant and animal parts to formulate ointments, powders, syrups and various other confections.1 Today, drug delivery technology can help improve patient adherence by simplifying the dosing regimen, and/or decreasing side effects. Other advantages include steadier drug concentrations in the bloodstream and targeted delivery of medication to its site of therapeutic action in the body.2

Non-GMO Project

It is important to choose suitable dosage forms for a given drug or nutritional product to be optimally effective; often, this requires a sufficient amount to be absorbed by the body at an appropriate rate. To achieve a therapeutic response after administration, attention must be given to bioavailability during the design of a new drug or nutraceuticals product because it may be adversely affected by the manufacturing operations and formulation components. Several core factors to consider:

1. What active ingredients are being delivered?

2. Safe, convenient delivery of accurate dosage

3. Rate of absorption (i.e. rapid onset or controlled release)

4. Concealing bitter or salty tastes or unappealing odors

5. Producing a dosage form that is easily identified—for example, by a distinct color and/or shape.

Solid Dose Forms

Solid dose forms (tablets, capsules, pills, powders, etc.) are more frequently used than any other forms, as they are non-invasive and generally more economical to prepare and self-administer. The challenge within the nutraceutical space is to keep up with the increasingly innovative dosage forms demanded by challenging APIs (active pharmaceutical ingredients) and changing patient populations.


The design and manufacture of tablets as a choice for OSD (oral solid dosage) is a complex process, whereby the formulation scientist must ensure the correct amount of drug substance, in the right form, is delivered at the appropriate time, at the proper rate and in the desired location with its chemical integrity protected to that point.

Tablets are commonly manufactured by wet granulation, dry granulation or direct compression. These methods, broadly, consist of a series of steps (unit processes)—weighing, milling, mixing, granulation, drying, compaction, (frequently) coating and packaging.


Two-piece hard shell capsules use is steadily increasing among pharma and nutra companies due to their accurate dosage capabilities, rapid release of medication due to expedited disintegration, odor and taste masking and custom appearance options such as capsule printing, custom colors and band sealing. Capsules sizes range from 000 to 5 (with 5 being the smallest) and are determined by formulation requirements. While it is important not to overfill capsules, a big plus is patient swallowability even with larger capsules.

The first step in estimating optimal capsule size for a given product is determining formulation density, a process utilizing tapped density for powders and bulk density for pellets, minitablets and granules. The appropriate capsule size can then be calculated using the formulation’s measured density, its target fill weight and capsule volume. The fill weight for liquids is calculated by taking the specific gravity of the liquid and the capsule body volume, then multiplying by a factor of 0.9.3

Liquid-filled Hard Capsule

Liquid-filled hard gelatin capsule technology was established in the early 1980s as an alternative to soft gelatin capsules. However, it turned out that hard capsules offer additional advantages that were valuable for certain consumers. For example, the remaining air bubble insight that two-piece capsules provide results in a visible liquid perceived as smooth and faster acting compared to a solid form. With the development of two-piece capsules from other polymers, such as HPMC, liquid-filled hard capsules have become more attractive in consumer health care due to the wide variety of options in product design and specific patient preferences.4-6

Until recently, soft gelatin capsules were the only dosage form available to encapsulate liquid and poorly water-soluble drug formulations in liquid vehicles.7 The addition of ACG’s capsule banding technology allows for the use of hard gelatin capsules or HPMC (hydroxypropyl methylcellulose) capsules as alternates to soft gelatin for filling liquid—as a bonus, it also can fill hot melt formulations (i.e. semi-solid) that are not feasible with soft gelatin technology.

Semisolid Dosage (Topical)

Topical dosage forms rely on external applications—either on the skin, to the mucous membrane (via eyes, nasal cavity or inner cheeks) or through suppositories for localized or systemic effects. The ointments, creams, pastes, jellies and emulsions are popular for their minimal side effects, avoidance of first-pass metabolism and ease of use. Topical formulations require different considerations during the development and manufacturing process. Factors to be considered include the specific targeted biologic surface and membrane as well as the target delivery performance, such as interactions with or absorption through skin. Other considerations include stability, compatibility and biocompatibility. A concise manufacturing process is imperative to ensure uniform products that contain the appropriate particle sizes and distributions of APIs and excipients in stable emulsions or suspensions.

Liquid Dosage Form

Liquid dosage forms are homogeneous liquids consisting of a solution, an emulsion or a suspension. This format has been widely recommended for decades for children and elderly patients due to dosage by body weight or age. However this requires, at minimum, a dosing device and the ability of patients or caretakers to dose correctly. In addition, multidose liquid formulations often require preservatives and taste-masking ingredients.

In recent years, the assumed ease of swallowing by in both pediatric and geriatric settings has come into question, as evidence has shown a preference for multi-particulates. Recently, the FDA (U.S. Food and Drug Administration) released guidelines on the use of soft food and drinks as a vehicle for administration of sprinkle formulations.

Aerosol Dosage Forms

Inhalation therapy was introduced about 100 years ago and became the standard in the treatment of COPD (chronic obstructive pulmonary disease) and asthma. In recent years, inhalation methods have successfully been incorporated for other applications, including pulmonary hypertension, cycstic fibrosis, vaccines and oncology.

There are three vehicles utilized to deliver a drug to the lungs: pressurized metered dose inhalers (pMDIs), nebulizers and dry powder inhalers (DPIs). Especially when rapid delivery and effects are desired, pMDIs play a key role; however, the increased instances of banning propellant systems have been limiting their application of late. For nasal delivery, drops or pump sprays are being used, helping to address issues related to poor bioavailability, slow absorption, drug degradation and mitigating adverse gastrointestinal tract events and first-pass metabolism in the liver.7-8

Dry powder inhalation (DPI) systems have gained substantial importance since the mid 1990s, and today are the most established dosage form for preventive treatment in pulmonary diseases. DPI systems are composed of an interactive powder blend or engineered particles delivered through a device component. Prefabricated multidose (e.g. cartridge) and monodose (e.g. blister) devices are available as well as monodosed capsules used with a very simple external device.9 Due to the simplicity in manufacturing and costs advantage, capsule-based DPI systems continue to gain popularity in both mature and emerging markets. NIE


1 Mestel, Rosie (2002-03-25). “The Colorful History of Pills Can Fill Many a Tablet.” LA Times. Archived from the original on 2015-09-19.

2 Rosen H, Abribat T. The rise and rise of drug delivery. Nature Rev Drug Discovery, 2005;4:381-385.

3 Hard Gelatin Capsules: Formulation and Manufacturing Considerations www.pharmapproach.com/hard-gelatin-capsules-formulation-and-manufacturing-considerations/2/.

4 Bowtle W, Materials, process and manufacturing considerations for lipid-based hard-capsule formats, Lipid-based formulations for oral drug delivery, Ed: D Hauss, Informa Healthcare, New York: pp 79-106, 2007.

5 Cole ET, Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into gelatin and non-gelatin capsules, Effective utilisation of lipid-based systems to enhance the delivery of poorly soluble drugs: physicochemical, biopharmaceutical and product development considerations, AAPS Workshop, Bethesda, 2007.

6 Rowley G, Filling of liquids and semi-solids into hard two-piece capsules, Pharmaceutical capsules, F Podczeck and BE Jones (eds), Pharmaceutical Press, London, 2nd edition, 9: pp 169-194, 2004.

7 Brox W, Zande H, Meinzer A. Soft gelatin capsule manufacture. EP 1993: 0 649- 651.

8 Djupesland, Per Gisle, Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review www.ncbi.nlm.nih.gov/pmc/articles/PMC3539067/.

9 3. A. Siew, BioPharm. Int. 31 (4) 10–13 (2018).

Evelyn Reinson is an international marketing manager at ACG, responsible for global marketing strategies of the company’s product range of capsules, films & foils, engineering, and inspection worldwide. www.ACG-world.com.