Pharmaceutical formulation

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Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.

Contents

Stages and timeline

Formulation studies involve developing a preparation of the drug which is both stable and acceptable to the patients. For orally administered drugs, this usually involves incorporating the drug into a tablet or a capsule. It is important to make the distinction that a tablet contains a variety of other potentially inert substances apart from the drug itself, and studies have to be carried out to ensure that the encapsulated drug is compatible with these other substances in a way that does not cause harm, whether direct or indirect.

Preformulation involves the characterization of a drug's physical, chemical, and mechanical properties in order to choose what other ingredients (excipients) should be used in the preparation. In dealing with protein pre-formulation, the important aspect is to understand the solution behavior of a given protein under a variety of stress conditions such as freeze/thaw, temperature, shear stress among others to identify mechanisms of degradation and therefore its mitigation. [1]

Formulation studies then consider such factors as particle size, polymorphism, pH, and solubility, as all of these can influence bioavailability and hence the activity of a drug. The drug must be combined with inactive ingredients by a method that ensures that the quantity of drug present is consistent in each dosage unit e.g. each tablet. The dosage should have a uniform appearance, with an acceptable taste, tablet hardness, and capsule disintegration.

It is unlikely that formulation studies will be complete by the time clinical trials commence. This means that simple preparations are developed initially for use in phase I clinical trials. These typically consist of hand-filled capsules containing a small amount of the drug and a diluent. Proof of the long-term stability of these formulations is not required, as they will be used (tested) in a matter of days. Consideration has to be given to what is known as "drug loading" - the ratio of the active drug to the total contents of the dose. A low drug load may cause homogeneity problems. A high drug load may pose flow problems or require large capsules if the compound has a low bulk density.

By the time phase III clinical trials are reached, the formulation of the drug should have been developed to be close to the preparation that will ultimately be used in the market. A knowledge of stability is essential by this stage, and conditions must have been developed to ensure that the drug is stable in the preparation. If the drug proves unstable, it will invalidate the results from clinical trials since it would be impossible to know what the administered dose actually was. Stability studies are carried out to test whether temperature, humidity, oxidation, or photolysis (ultraviolet light or visible light) have any effect, and the preparation is analysed to see if any degradation products have been formed.

Container closure

Formulated drugs are stored in container closure systems for extended periods of time. These include blisters, bottles, vials, ampules, syringes, and cartridges. The containers can be made from a variety of materials including glass, plastic, and metal. The drug may be stored as a solid, liquid, or gas.

It's important to check whether there are any undesired interactions between the preparation and the container. For instance, if a plastic container is used, tests are carried out to see whether any of the ingredients become adsorbed on to the plastic, and whether any plasticizer, lubricants, pigments, or stabilizers leach out of the plastic into the preparation. Even the adhesives for the container label need to be tested, to ensure they do not leach through the plastic container into the preparation.

Formulation types

The drug form varies by the route of administration. Like capsules, tablets, and pills etc.

Enteral formulations

Oral drugs are normally taken as tablets or capsules.

The drug (active substance) itself needs to be soluble in aqueous solution at a controlled rate. Such factors as particle size and crystal form can significantly affect dissolution. Fast dissolution is not always ideal. For example, slow dissolution rates can prolong the duration of action or avoid initial high plasma levels. Treatment of active ingredient by special ways such as spherical crystallization [2] can have some advantages for drug formulation.

Tablet

A tablet is usually a compressed preparation that contains:

The dissolution time can be modified for a rapid effect or for sustained release.

Special coatings can make the tablet resistant to the stomach acids such that it only disintegrates in the duodenum, jejunum and colon as a result of enzyme action or alkaline pH.

Pills can be coated with sugar, varnish, or wax to disguise the taste. Pharmaceutical ingredients such as APIs can also be coated with a ResonantAcoustic mixer for controlled release and taste-masking. [3]

Capsule

A capsule is a gelatinous envelope enclosing the active substance. Capsules can be designed to remain intact for some hours after ingestion in order to delay absorption. They may also contain a mixture of slow and fast release particles to produce rapid and sustained absorption in the same dose.

Sustained release

There are a number of methods by which tablets and capsules can be modified in order to allow for sustained release of the active compound as it moves through the digestive tract. One of the most common methods is to embed the active ingredient in an insoluble porous matrix, such that the dissolving drug must make its way out of the matrix before it can be absorbed. In other sustained release formulations the matrix swells to form a gel through which the drug exits.

Another method by which sustained release is achieved is through an osmotic controlled-release oral delivery system, where the active compound is encased in a water-permeable membrane with a laser drilled hole at one end. As water passes through the membrane the drug is pushed out through the hole and into the digestive tract where it can be absorbed.

Parenteral formulations

These are also called injectable formulations and are used with intravenous, subcutaneous, intramuscular, and intra-articular administration. The drug is stored in liquid or if unstable, lyophilized form.

Many parenteral formulations are unstable at higher temperatures and require storage at refrigerated or sometimes frozen conditions. The logistics process of delivering these drugs to the patient is called the cold chain. The cold chain can interfere with delivery of drugs, especially vaccines, to communities where electricity is unpredictable or nonexistent. NGOs like the Gates Foundation are actively working to find solutions. These may include lyophilized formulations which are easier to stabilize at room temperature.

Most protein formulations are parenteral due to the fragile nature of the molecule which would be destroyed by enteric administration. Proteins have tertiary and quaternary structures that can be degraded or cause aggregation at room temperature. This can impact the safety and efficacy of the medicine. [4]

Liquid

Liquid drugs are stored in vials, IV bags, ampoules, cartridges, and prefilled syringes.

As with solid formulations, liquid formulations combine the drug product with a variety of compounds to ensure a stable active medication following storage. These include solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers/reducers, surfactants, chelating agents, and adjuvants.

If concentrated by evaporation, the drug may be diluted before administration. For IV administration, the drug may be transferred from a vial to an IV bag and mixed with other materials.

Lyophilized

Lyophilized drugs are stored in vials, cartridges, dual chamber syringes, and prefilled mixing systems.

Lyophilization, or freeze drying, is a process that removes water from a liquid drug creating a solid powder, or cake. The lyophilized product is stable for extended periods of time and could allow storage at higher temperatures. In protein formulations, stabilizers are added to replace the water and preserve the structure of the molecule. [5]

Before administration, a lyophilized drug is reconstituted as a liquid before being administered. This is done by combining a liquid diluent with the freeze-dried powder, mixing, then injecting. Reconstitution usually requires a reconstitution and delivery system to ensure that the drug is correctly mixed and administered.

Topical formulations

Cutaneous

Options for topical formulation include: [6]

See also

Related Research Articles

<span class="mw-page-title-main">Tablet (pharmacy)</span> Drug delivery form in which the ingredients are solidified for later consumption

A tablet is a pharmaceutical oral dosage form or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume.

<span class="mw-page-title-main">Topical medication</span> Medication applied to body surfaces

A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. The word topical derives from Greek τοπικόςtopikos, "of a place".

An excipient is a substance formulated alongside the active ingredient of a medication. They may be used to enhance the active ingredient’s therapeutic properties; to facilitate drug absorption; to reduce viscosity; to enhance solubility; to improve long-term stabilization ; or to add bulk to solid formulations that have small amounts of potent active ingredients. During the manufacturing process, excipients can improve the handling of active substances and facilitate powder flow. The choice of excipients depends on factors such as the intended route of administration, the dosage form, and compatibility with the active ingredient.

<span class="mw-page-title-main">Freeze drying</span> Low temperature dehydration process

Freeze drying, also known as lyophilization or cryodesiccation, is a low temperature dehydration process that involves freezing the product and lowering pressure, thereby removing the ice by sublimation. This is in contrast to dehydration by most conventional methods that evaporate water using heat.

An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals.

<span class="mw-page-title-main">Capsule (pharmacy)</span> Relatively stable shell containing medicine

In the manufacture of pharmaceuticals, encapsulation refers to a range of dosage forms—techniques used to enclose medicines—in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are:

Dosage forms are pharmaceutical drug products presented in a specific form for use. They contain a mixture of active ingredients and inactive components (excipients), configured in a particular way and apportioned into a specific dose. For example, two products may both be amoxicillin, but one may come in 500 mg capsules, while another may be in 250 mg chewable tablets.

<span class="mw-page-title-main">Compounding</span> Preparation of a custom medication

In the field of pharmacy, compounding is preparation of custom medications to fit unique needs of patients that cannot be met with mass-produced products. This may be done, for example, to provide medication in a form easier for a given patient to ingest, or to avoid a non-active ingredient a patient is allergic to, or to provide an exact dose that isn't otherwise available. This kind of patient-specific compounding, according to a prescriber's specifications, is referred to as "traditional" compounding. The nature of patient need for such customization can range from absolute necessity to individual optimality to even preference.

<span class="mw-page-title-main">Orally disintegrating tablet</span> Pill that dissolves on contact with saliva

An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole. The ODT serves as an alternative dosage form for patients who experience dysphagia or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population and 18-22% of all patients in long-term care facilities ODTs may have a faster onset of effect than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription.

Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body.

<span class="mw-page-title-main">Thin-film drug delivery</span> Drug delivery method

Thin-film drug delivery uses a dissolving film or oral drug strip to administer drugs via absorption in the mouth and/or via the small intestines (enterically). A film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made.

Transmission Raman spectroscopy (TRS) is a variant of Raman spectroscopy which is advantageous in probing bulk content of diffusely scattering samples. Although it was demonstrated in the early days of Raman spectroscopy it was not exploited in practical settings until much later, probably due to limitations of technology at the time. It was rediscovered in 2006, where the authors showed that it was capable of allowing Raman spectroscopy through many millimetres of tabletted or powdered samples. In addition, this research has also identified several highly beneficial analytical properties of this approach, including the ability to probe bulk content of powders and tissue in the absence of subsampling and to reject Raman and fluorescence components originating from the surface of the sample.

<span class="mw-page-title-main">Pharmaceutical manufacturing</span> Synthesis of pharmaceutical drugs

Pharmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as part of the pharmaceutical industry. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, granulation, coating, tablet pressing, and others.

<span class="mw-page-title-main">Drug packaging</span> Packaging for pharmaceutical preparations

Drug packaging is process of packing pharmaceutical preparations for distribution, and the physical packaging in which they are stored. It involves all of the operations from production through drug distribution channels to the end consumer.

<span class="mw-page-title-main">Tableting</span> Method of pressing medicine or candy into tablets

Tableting is a method of pressing medicine or candy into tablets. Confectionery manufacture shares many similarities with pharmaceutical production.

<span class="mw-page-title-main">Effervescent tablet</span> Tablets to release carbon dioxide in water

Effervescent or carbon tablets are tablets which are designed to dissolve in water and release carbon dioxide. The carbon dioxide is generated by a reaction of a compound containing bicarbonate, such as sodium bicarbonate or magnesium bicarbonate, with an acid such as citric acid or tartaric acid. Both compounds are present in the tablet in powder form and start reacting as soon as they dissolve in water.

<span class="mw-page-title-main">Glyceryl behenate</span> Chemical compound

Glyceryl behenate is a fat used in cosmetics, foods, and oral pharmaceutical formulations. In cosmetics, it is mainly used as a viscosity-increasing agent in emulsions.

<span class="mw-page-title-main">Vaccine ingredients</span> Ingredients used in a vaccine dose

A vaccine dose contains many ingredients very little of which is the active ingredient, the immunogen. A single dose may have merely nanograms of virus particles, or micrograms of bacterial polysaccharides. A vaccine injection, oral drops or nasal spray is mostly water. Other ingredients are added to boost the immune response, to ensure safety or help with storage, and a tiny amount of material is left-over from the manufacturing process. Very rarely, these materials can cause an allergic reaction in people who are very sensitive to them.

<span class="mw-page-title-main">Topical cream formulation</span>

Topical cream formulation is an emulsion semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and volatiles and/or less than 50 per cent of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external skin application. In a topical cream formulation, ingredients are dissolved or dispersed in either a water-in-oil (W/O) emulsion or an oil-in-water (O/W) emulsion. The topical cream formulation has a higher content of oily substance than gel, but a lower content of oily ingredient than ointment. Therefore, the viscosity of topical cream formulation lies between gel and ointment. The pharmacological effect of the topical cream formulation is confined to the skin surface or within the skin. Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. Topical cream formulation is used for a wide range of diseases and conditions, including atopic dermatitis (eczema), psoriasis, skin infection, acne, and wart. Excipients found in a topical cream formulation include thickeners, emulsifying agents, preservatives, antioxidants, and buffer agents. Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of active substances, and homogenization of the product mixture.

A 3D printed medication is a customized medication created using 3D printing techniques, such as 3D printed tablets. It allows for precise control over the composition and dosage of drugs, enabling the production of personalized medicine tailored to an individual's specific needs, such as age, weight, and medical condition. This approach can be used to improve the effectiveness of drug therapies and to reduce side effects.

References

  1. Simler, R., Walsh, G., Mattaliano, R.J., Guziewicz, N., and Perez-Ramirez, B. (2008). Maximizing Data Collection and Analysis During Preformulation of Biotherapeutic Proteins. BioProcess International 6(10), 38-45.
  2. M. Nocent, L. Bertocchi, F. Espitalier, M. Baron and G. Couarraze. (2001). Definition of a solvent system for spherical crystallization of salbutamol sulfate by quasi-emulsion solvent diffusion (QESD) method. Journal of Pharmaceutical Sciences 90 (10), 1620-1627.
  3. "Solventless mixing process for coating pharmaceutical ingredients". Google Patents. 2013-10-09. Retrieved 2024-11-21.
  4. Chang, B.S. and Hershenson, S. 2002. Practical approaches to protein formulation development. in "Rationale Design of stable protein formulations-theory and practice" (J.F. Carpenter and M.C. Manning eds.) Kluwer Academic/Plenum publishers, New York, pp. 1-25
  5. Rationale Design of Stable Lyophilized Protein Formulations: Some Practical Advice, Carpenter et al, Pharmaceutical Research, Vol 14, No.8, 1977
  6. "Doctor, why are you prescribing an ointment?". American Academy of Dermatology.