1

lipid-based delivery systems for oral

administration • Lipid-based delivery systems range from simple oil

solutions to complex mixtures of oils, surfactants, co-surfactants and cosolvents.

• The latter mixtures are typically self-dispersing systems often referred to as self-emulsifying drug delivery systems (SEDDS) or self-microemulsifying drug delivery systems (SMEDDS)

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lipid-based delivery systems for oral

administration • Formulations which disperse to form transparent

colloidal systems are usually referred to as SMEDDS, though in scientific terms this distinction is somewhat arbitrary.

• Whether these dispersions are thermodynamically stable microemulsions is usually unknown, though the dispersions formed by both SEDDS and SMEDDS are often stable in practice for months.

• he particle sizes of dispersions formed by SMEDDS are lower than those formed by SEDDS.

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lipid-based delivery systems for oral

administration • The performance of lipid-based delivery systems is

governed by their fate in the gastrointestinal tract, rather than the particle size of the initial dispersion.

• This concept can be appreciated by considering the fate of long-chain triglycerides, which have no practical ability to self-disperse but are digested rapidly in the intestine.

• Subsequent to lipolysis their fatty acid and monoglyceride digestion products are solubilised by bile salt–lecithin mixed micelles, a fine colloidal dispersion which promotes absorption and.

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lipid-based delivery systems for oral

administration • It is likely that the powerful digestive system in the

intestine will play a part in determining the fate of all lipid-based delivery systems.

• Even when non-digestible excipients are used the interaction of a dispersed formulation with bile is likely to change its physical form.

• Formulators need to have a good understanding of gastrointestinal digestion and are increasingly making use of relevant in vitro tests which can predict the fate of the formulation, and most importantly the drug, after oral administration

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The Lipid Formulation Classification System

• The Lipid Formulation Classification System (LFCS) main purpose is to enable in vivo studies to be interpreted more readily, and subsequently to facilitate the identification of the most appropriate formulations for specific drugs, i.e. with reference to their

physicochemical properties

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The Lipid Formulation Classification System

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The Lipid Formulation Classification System

• Many of the marketed products are Type III systems but this group is particularly diverse as a result of the wide variation in the proportions of oily and water-soluble materials used

• This group has been further divided into Type IIIA and Type IIIB, to distinguish between formulations which contain a significant proportion of oils (Type IIIA) and

those which are predominantly water-soluble (Type IIIB).

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The Lipid Formulation Classification System

• At present the sub-classification of Types III formulations is ill-defined, particularly when one considers that a Type III formulation could contain 3–5 excipients, including water-insoluble and water-soluble surfactants, as well as water miscible cosolvents.

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The Lipid Formulation Classification System

• Precipitation of a lipophilic drug after 1/100 dilutions of Types II, IIIA, IIIB and IV lipid-based formulations of the drug in water. The graph shows the % of the dose of drug which remained in solution (mean ± s.d. n = 4) as a function of time after initial dispersion. Prior to dispersion the drug was dissolved at 80% saturated solubility in each formulation. Formulations: Type II—15% w/w Miglyol 812, 35% Imwitor 988, 50% Tween 85; Type IIIA—15% w/w Miglyol 812, 35% Imwitor 988, 50% Tween 80; Type IIIB—50% Imwitor 308, 50%

Tween 80; Type IV—50% Tween 80, 50% propylene glycol.

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Excipients for lipid formulations • A wide range of triglycerides, partial glycerides,

semi-synthetic oily esters, and semi-synthetic non-ionic surfactants esters are available from excipient

suppliers.

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Excipients for lipid formulations

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Excipients for lipid formulations • Water-insoluble surfactants penetrate and fluidize

biological membranes and water-soluble surfactants have the potential to solubilize membrane components.

• All surfactants are potentially irritant or poorly tolerated as a result of these non-specific effects.

• In general terms cationic surfactants are more toxic than anionic surfactants which in turn are more toxic than

non-ionic surfactants.

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Excipients for lipid formulations • Lipid-based delivery systems usually only include non-

ionic surfactants so it is pertinent to compare the toxicity of non-ionic surfactants.

• In general bulky surfactants such as polysorbates (derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids) or polyethoxylated vegetable oils (Cremophor EL®) are less toxic than single-chain surfactants, and esters are less toxic than ethers (which are non-digestible).

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Excipients for lipid formulations • Non-ionic surfactants are generally considered to be

acceptable for oral ingestion.

• The oral and intravenous LD50 values for most non-ionic surfactants are in excess of 50 g/Kg and 5 g/Kg respectively, so 1 g surfactant in a formulation is well-tolerated for uses in acute oral drug administration.

• More careful consideration needs to be given to formulation of a product which is intended for chronic use, and it is noteworthy that most marketed lipid products for chronic use generally do not include surfactants

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Excipients for lipid formulations • However the marketed HIV protease inhibitors products,

such as Agenerase (Amprenavir), Kaletra (lopinavir and ritonavir) and Norvir (ritonavir), contain a considerable mass of surfactants in each capsule, and several capsules are administered 2–4 times daily, so that patients are ingesting 2–3 g Cremophor or TPGS (Tocopheryl polyethylene glycol 1000 succinate ) daily.

• Sandimmune® Neoral® Capsules.

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Excipients for lipid formulations • Although most non-ionic surfactants have similar LD50

values, in practice formulators are predictably cautious when choosing surfactants and usually turn to one of a few tried and tested materials which have been used in marketed products.

• In this respect a useful resource is the US FDA Center for Drug Evaluation and Research ‘Inactive Ingredients Database’ which states the masses or concentrations of ingredients used in marketed pharmaceutical products.

• http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm

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Excipients for lipid formulations • Another practical consideration relates to the chemical

complexity of excipients.

• The use of vegetable oils from different plants is an immediate source of diversity, and subsequent chemical derivation by hydrolysis and esterification introduces more diversity.

• Further processing is required to produce non-ionic surfactants, usually esters of polyoxyethylene or polyglycerol, or products of reaction with ethylene oxide.

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Excipients for lipid formulations • The polyoxyethylene or polyglycerol chains are

polymeric in nature, which means that a typical surfactant product based on mixed glycerides is comprised of dozens of separate chemical entities in different proportions.

• For practical purposes these products are usually given a simple chemical name which represents their ‘average’ composition but which hides their complexity.

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Polyglycerol monooleate n=2 or 3

Polyglycerol mono laaurate n = 2 or 3

HO-CH2-(CH2-O-CH2-)n-CH2-OH

Polyoxyethylene

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Excipients for lipid formulations • The formulator of lipid-based products has to accept that

there will be differences between excipient products which appear to have the same chemical name, and there will also be a finite level of diversity between batches of the same product.

• Establishing a relationship with the excipient suppliers to set product specifications is an important strategy, but the formulator should also build a degree of latitude حرية

الختيارا into formulation design (robustness), so that the product is not compromised by inevitable variation in chemical composition of the excipients used.

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Excipients for lipid formulations • Trace contaminants are an issue with lipid excipients

and surfactants, particularly in relation to the chemical stability of the dissolved drug.

• Care should be taken to select excipients with low level of peroxides, aldehydes etc. and to ascertain at an early stage in preformulation studies whether the drug of interest is sensitive to the presence of particular trace contaminants.

• Chemical stability of drugs in lipid vehicles is poorly understood. Formulators should exercise caution but the prevalence of stability problems is not clear from the published literature.

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Triglycerides

• Triglyceride vegetable oils have many advantages as the foundation of lipid-based delivery systems: They are commonly ingested in food, fully digested and absorbed, and therefore do not present any safety issues.

• Vegetable oils are glyceride esters of mixed unsaturated long-chain fatty acids, commonly known as long-chain triglycerides (LCT).

• Oils from different vegetable sources have different proportions of each fatty acid.

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Triglycerides

• The fatty acid compositions of coconut and palm kernel oils are noteworthy in that they are unusually rich in saturated medium-chain oils (C8, C10 and particularly C12).

• Coconut oil is distilled to produce the generic product ‘medium-chain triglycerides’ (MCT) (also known as glyceryl tricaprylate/caprate) which is available from several suppliers and commonly comprises glyceryl esters with predominantly saturated C8 (50–80%) and C10 (20–45%) fatty acids.

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Triglycerides

• Triglycerides are highly lipophilic and their solvent capacity for drugs is commonly a function of the effective concentration of the ester groups, thus on a weight basis MCT generally has higher solvent capacity than LCT.

• In addition MCT is not subject to oxidation, so MCT is a popular choice for use in lipid-based products.

• Castor oil is noteworthy as the only common source of glyceryl ricinoleate, which uniquely has a hydroxyl group coupled to the alkyl chain.

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Mixed glycerides and polar oils

• Partial hydrolysis of triglycerides is used to produce a wide range of mixed glyceride excipients, containing various proportions of monoglycerides, diglycerides and triglycerides.

• The chemical composition of mixed glyceride products depends on the source of triglyceride starting material as well as the extent of hydrolysis induced.

• Care needs to be taken with excipient names. ‘Monoglyceride’ products often contain substantial quantities of diglycerides and triglycerides, so the manufacturers datasheet should be consulted in detail.

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Mixed glycerides and polar oils

• ‘Glyceryl monooleate’ is a waxy material but its physical form will be very dependent on the di-and trigyceride content.

• Since waxes create technical challenges, mixed mono and diglycerides of long-chain fatty acids are a good option, allowing liquid formulations to be produced.

• Trace amounts of saturated monoglycerides sometimes produce a hazy product.

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Mixed glycerides and polar oils

• In general, mixed long-chain glycerides are popular excipients. They are usually much better solvents for drugs than triglycerides, unless the drug is highly lipophilic, and they are also useful components of Type II and Type III self-emulsifying systems, promoting mutual miscibility and emulsification.

• Medium-chain mixed glycerides have become popular excipients, having even greater solvent capacity, enhanced ability to promote emulsification, and lack of susceptibility to oxidation.

• However there are complications with medium-chain excipients in relation to digestion.

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Mixed glycerides and polar oils• In addition to mixed glycerides there are a wide variety of related

materials which may be useful, including esters of propylene glycol, and esters formed between fatty acids and fatty alcohols.

• Other more polar oily excipients are of interest to improve the solvent capacity and dispersibility of the formulation. Some excipients which are traditionally thought of as hydrophobic surfactants, such as sorbitan fatty acid esters (Spans), are very similar in physical properties to mixed glycerides or propylene glycol esters.

• The more lipophilic sorbitan fatty acid esters, such as sorbitan trioleate (Span 85) are alternative polar oils.

• Sorbitan monooleate (Span 80) which has more hydroxyl groups has also been used widely in pharmaceutical products.

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Mixed glycerides and polar oils

• In the context of formulation and the desire to promote mutual miscibility, free fatty acids can be considered to belong to this general group of polar oils or ‘co-surfactants’.

• Oleic acid has been used in a number of marketed products.

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Water-insoluble surfactants

• Non-ionic esters which are not polyethoxylated or polyglycerylated can be considered to be polar oils.

• In the context of oral lipid-based formulations we refer to a group of excipients of intermediate HLB (8–12), which adsorb strongly at oil–water interfaces, as ‘water-insoluble surfactants’.

• These materials are insufficiently hydrophilic to dissolve in water and form micelles but nevertheless are sufficiently hydrophilic to be capable of driving self-emulsification.

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Water-insoluble surfactants

• The constituents of water-insoluble surfactants will have a finite solubility in water depending on their degree of ethoxylation, but solubility is generally very low.

• These surfactants are sometimes described as ‘dispersible’ in water, meaning that they can form an emulsion if subject to shear. These materials typically are predominantly oleate esters, such as polyoxyethylene (20) sorbitan trioloeate (polysorbate 85—‘Tween 85’) or polyoxyethylene (25) glyceryl trioleate (‘Tagat TO’).

• These two examples have HLB values between 11 and 11.5 and are particularly useful for formulation of Type II systems.

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Water-insoluble surfactants• It should be noted that the properties of these

surfactants cannot necessarily be recreated by blending materials of different HLB values.

• Polysorbate 80 can be blended with sorbitan monooleate (i.e. classical Tween 80/Span80 mixtures) to give a average HLB of 11 but such a blend will contain a mixture of water-soluble and water-insoluble molecules, and will not behave in the same way as Tween 85 which consists predominantly of water-insoluble molecules.

• Tween 85 is polymeric so it will contain a finite fraction of water-soluble components, but this fraction will not dominate the fate of the formulation components after dispersion or digestion.

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Water-soluble surfactants• The most commonly used surfactants for formulation of

SEDDS or SMEDDS are water-soluble, though by definition these materials can only be used in Type III or Type IV formulations.

• Above their critical micelle concentration these materials dissolve in pure water at low concentrations to form micellar solutions.

• This implies an HLB value of approximately 12 or greater. The fatty acid components can be either

unsaturated or saturated.

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Water-soluble surfactants• The popular castor oil derivative Cremophor RH40, is a

typical example of a product with saturated alkyl chains resulting from hydrogenation of materials derived from a vegetable oil.

• Its close relative Cremophor EL, which has also been used widely, has a slightly lower degree of ethoxylation but is not hydrogenated and is therefore unsaturated.

• Relatively few of the available water-soluble ester surfactants have been used in pharmaceutical products. This is a function of their proven safety profile rather than particular advantages they offer in physicochemical performance.

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Water-soluble surfactants• One intriguing issue in relation to oral bioavailability which has not

been satisfactorily resolved is the extent to which bioavailability is affected by direct effects of surfactants on drug efflux by P-glycoprotein.

• Cremophors have been implicated as inhibitors of efflux pumps, but the mechanism of inhibition has not been determined.

• This could be a non-specific conformational change caused by penetration of surfactant molecules into the plasma membrane, adsorption of surfactants to the external surface of the efflux pump, or even interaction of small molecules with the intracellular domains of the efflux pump.

• The chemical heterogeneity of surfactants such as Cremophors will make it difficult to establish a precise mechanism.

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Co solvents• Several marketed lipid-based products contain water-

soluble cosolvents.

• The most popular materials have been PEG 400, propylene glycol, ethanol and glycerol, though other approved cosolvents have been used in experimental

studies.

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Co solvents• There are at least three reasons why cosolvents have

been included in lipid-based formulations:– Ethanol was used in early cyclosporin products at a low

concentration to aid dissolution of the drug during manufacture. – More commonly it has been assumed that cosolvents could be

included to increase the solvent capacity of the formulation for drugs which dissolve freely in cosolvents. However to enhance the solvent capacity significantly the cosolvent must be present at high concentration and this is associated with the risk of drug precipitation when the formulation is dispersed in water. Cosolvents lose their solvent capacity quickly following dilution. For many drugs the relationship between cosolvent concentration and solubility is near to logarithmic.

– A third reason for inclusion of cosolvents is to aid dispersion of systems which contain a high proportion of water-soluble surfactants. There are practical limits on the concentrations of cosolvents which can be used, governed by issues of immiscibility with oil components and also possible incompatibilities of low molecular weight cosolvents with capsule shells.

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Additives

• Lipid-soluble antioxidants such as -tocopherol, β-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or propyl gallate could potentially be included in formulations to protect either unsaturated fatty acid chains or drugs from oxidation.

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Choice of Excipients-Mutual Miscibility• Mutual miscibility of excipients is necessary to produce a clear,

stable, liquid formulation.

• LCT oils are not usually miscible with hydrophilic surfactants or cosolvents so in practice it is often necessary to blend these materials with a polar oil (or co-surfactant) to promote mutual solubility for Type III systems.

• The inclusion of polar oils, such as mixed glycerides, usually has the added benefit of enhancing dispersion of Type III systems.

• Water-insoluble surfactants are usually miscible with MCT and LCT oils so that Type II systems can be formulated with just these two components. Nevertheless polar oils can be added to optimise the performance of Type II systems.

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Choice of Excipients-Mutual Miscibility• Interestingly the affinity of mixed glycerides for both lipophilic and

more polar materials allows mutual solubility to be achieved using three-component mixtures of MCT oils, medium-chain mono/diglycerides and cosolvents.

• The chemical diversity of lipid excipients can lead to immiscibility on long-term storage, so long-term physical stability tests should be carried out routinely during commercial development projects.

• Problems may result from the common practice of heating waxy excipients prior to and during blending. This can lead to dissolution of saturated fatty acid components at elevated temperature, leading to supersaturation at ambient temperature. Re-crystallization of the waxy components may take weeks or months once excipients have been blended.

• Temperature cycling tests may help to identify potential problems with supersaturation, but anticipation of potential problems is vital.

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Choice of Excipients-Solvent Capacity• Triglycerides are poor solvents for all but highly lipophilic

compounds, so most lipid-based formulations contain polar oils, surfactants and/or cosolvents to improve the solvent capacity of the anhydrous formulation.

• Many poorly-water soluble drugs are much more soluble in cosolvents than oils, and such compounds also dissolve in the polyoxyethylene-rich environment present in water-soluble non-ionic surfactant materials.

• This naturally encourages formulators to add water-soluble surfactants and cosolvents at the expense of lipids, ultimately resulting in the complete exclusion of lipid excipients to produce Type IV formulations.

• The formulator must balance the advantage of including cosolvents with the risk of inducing drug precipitation on dispersion.

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Choice of Excipients-Capsule compatibility • Low molecular weight polar molecules present in capsule

formulations are able to penetrate and plasticize gelatin capsule shells, which restricts the concentration of propylene glycol and related cosolvents that can be used in capsule fills.

• Surfactants can also destabilise capsule shells.

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Solid self-emulsifying drug delivery system • SEDDS can exist in either liquid or solid states.

• SEDDS are usually, however, limited to liquid dosage forms, because many excipients used in SEDDS are not solids at room temperature.

• Given the advantages of solid dosage forms, S-SEDDS have been extensively exploited in recent years, as they frequently represent more effective alternatives to conventional liquid SEDDS.

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Solid self-emulsifying drug delivery system • From the perspective of dosage forms, S-SEDDS mean

solid dosage forms with self-emulsification properties.

• S-SEDDS focus on the incorporation of liquid/semisolid SE ingredients into powders/nanoarticles by different solidification techniques (e.g. adsorptions to solid carriers, spray drying, melt extrusion, nanoparticle technology, and so on).

• To some extent, S-SEDDS are combinations of SEDDS and solid dosage forms, so many properties of S-SEDDS (e.g. excipients selection, specificity, and characterization) are the sum of the corresponding properties of both

SEDDS and solid dosage forms.

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Solidification techniques for transforming

liquid/semisolid SEDDS to S-SEDDS • Spray cooling • Spray drying • Adsorption to solid carriers • Melt granulation

• Melt extrusion/extrusion spheronization

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Spray cooling • Spray cooling also referred to as spray congealing is a

process whereby the molten formula is sprayed into a cooling chamber.

• Upon contact with the cooling air, the molten droplets congeal and re-crystallize into spherical solid particles that fall to the bottom of the chamber and subsequently collected as fine powder.

• The fine powder may then be used for development of solid dosage forms — tablets or direct filling into hard shell capsules.

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Spray cooling • The main parameters for spray cooling are:

– the melting point of the excipient that should range between 50 and 80 °C,

– the viscosity of the formulation during atomization,

– and the cooling air temperature inside the atomizer to allow a quick and complete crystallization of droplets.

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Spray cooling • The spray cooling technique can be used for

bioavailability enhancement and or sustained release formulations — depending on the choice of lipid matrix, and the drug behavior in that matrix (solution or dispersion).

• The drug loading capacity is limited by formulation viscosity as dispersions generally tend to be more viscous than solutions. A maximum of 30% drug loading capacity has been reported in the literature

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Spray cooling • The main class of excipient used with this technique are

polyoxylglycerides and more specifically stearoyl polyoxylglycerides (Gelucire® 50/13) facilitating the production of microparticles with narrow size distribution that exhibit significantly enhanced drug release profiles

for poorly soluble drugs.

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Spray drying • Spray drying is defined as a process by which a liquid

solution is sprayed into a hot air chamber to evaporate the volatile fraction, i.e. the organic solvent or the water contained in an emulsion.

• The process yields solid microparticles.

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Spray drying • This technique involves the preparation of a formulation by

mixing lipids, surfactants, drug, solid carriers, and solubilization/dispersing them in an organic / aqueous phase before spray drying.

• The liquid formulation is then atomized into a spray of droplets. The droplets are introduced into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporates, forming dry particles under controlled temperature and airflow conditions.

• Such particles can be further prepared into tablets or capsules.

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Spray drying • The conventional organic solvent used in spray drying is

dichloromethane, a harmful solvent that could be carcinogenic. However, other solvents could be used with that technique.

• If the formula is dispersed (emulsified with an aqueous phase), the product is referred to as a dry emulsion.

• Dry emulsion technology solves the stability problems associated with classic emulsions (phase separation, contamination by microorganism, etc.) during storage and helps also avoid using harmful or toxic organic solvents. Dry emulsions may be redispersed into water before use.

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Spray drying • The atomizer, the temperature, the most suitable airflow

pattern and the drying chamber design are selected according to the drying characteristics of the product and powder specification.

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Adsorption to solid carriers • Free flowing powders may be obtained from liquid SE

formulations by adsorption to solid carriers.

• The adsorption process is simple and just involves addition of the liquid formulation onto carriers by mixing in a blender.

• The resulting powder may then be filled directly into capsules or, alternatively, mixed with suitable excipients before compression into tablets.

• A significant benefit of the adsorption technique is good content uniformity.

• SEDDS can be adsorbed at high levels (up to 70% (w/w)) onto suitable carriers

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Adsorption to solid carriers • Solid carriers can be:– Microporous inorganic substances, – High-surface-area colloidal inorganic adsorbent

substances, – Cross-linked polymers– Nanoparticle adsorbents,

• For example, silica, silicates, magnesium trisilicate, magnesium hydroxide, talcum, crospovidone, cross-linked sodium carboxymethyl cellulose and cross-linked polymethyl methacrylate, porous silicon dioxide (Sylysia 550), carbon nanotubes, carbon nanohorns, fullerene, charcoal and bamboo charcoal have been used.

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Adsorption to solid carriers • These carriers should be selected for their ability to:– Adsorb a great quantity of liquid excipients (to allow for a high drug

loading and high lipid exposure) and for – the flowability of the mixture after adsorption.

• The down side of this formulation technique however, may be the reduced drug loading capacity in the final dosage form. This is due initially to dilution of the lipid formulation during mixing with the solid carrier and subsequent dilution by addition of excipients to obtain compressible mixtures for tableting.

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Melt granulation• As a ‘one-step’ operation, melt granulation offers several

advantages compared with conventional wet granulation, since the liquid addition and the subsequent drying phase are omitted.

• Moreover, it is also a good alternative to the use of

solvent.

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Melt granulation• The technique necessitates high shear mixing in presence

of a meltable binder which may be sprayed in molten state onto the powder mix as in classic wet granulation process.

• This is referred to as “pump-on” technique.

• Alternatively, the binder may be blended with the powder mix in its solid or semi-solid state and allowed to melt (partially or completely) by the heat generated from the friction of particles during high shear mixing — referred to as “melt-in” process.

• The melted binder forms liquid bridges with the powder particles that shape into small agglomerates (granules) which can, by further mixing under controlled conditions transform to spheronized pellets.

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Melt granulation

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Melt granulation

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Melt granulation• The progressive melting of the binder allows the control

of the process and the selection of the granule's size.

• Variations of this technique have also been reported in the literature. For example, fluid bed equipment outfitted with a rotor may be used as an alternative technique to produce pellets by melt granulation.

• Also, the melt granulation process may be used for adsorbing semi-solid self-emulsifying systems on solid neutral carriers (mainly silica and magnesium aluminometasilicate).

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Melt granulation

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Melt granulation• The melt granulation technique, also described as

“thermoplastic pelletization”, is effortlessly adaptable to lipid-based excipients that exhibit thermoplastic properties.

• A wide range of solid and semi-solid lipids can be applied as meltable binder for solid dispersions.

• Generally, lipids with low HLB and high melting point are suitable for sustained release applications.

• Semi-solid excipients with high HLB on the other hand may serve in immediate release and bioavailability enhancement.

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Melt granulation• A wide range of solid and semisolid lipids can be applied

as meltable binders.

• Gelucire®, a family of vehicles derived from the mixtures of mono-/di-/tri-glycerides and polyethylene glycols (PEG) esters of fatty acids, is able to further increase the dissolution rate compared with PEG usually used before, probably owing to its SE property.

• Other lipid-based excipients evaluated for melt granulation to create solid SES include lecithin, partial glycerides, or polysorbates.

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Melt granulation The melt granulation process was usually used for

adsorbing SES (lipids, surfactants, and drugs) onto solid neutral carriers (mainly silica and magnesium aluminometa silicate)

The main parameters that control the granulation process are impeller speed, mixing time, binder particle size, and the viscosity of the binder.

The main advantages of melt granulation/pelletization with lipids are: Process simplicity (one-step) Absence of solvents The potential for the highest drug loading capacity − 85%

theoretically, and up to 66% actually reported in the literature.

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Melt extrusion/extrusion spheronization

• Extrusion is a procedure of converting a raw material with plastic properties into a product of uniform shape and density, by forcing it through a die under controlled temperature, product flow, and pressure conditions.

• The size of the extruder aperture will determine the approximate size of the resulting spheroids.

• The extrusion–spheronization process is commonly used in the pharmaceutical industry to make uniformly sized spheroids (pellets).

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Melt extrusion/extrusion spheronization

• The extrusion–spheronization process requires the following steps: – dry mixing of the active ingredients and excipients to

achieve a homogenious powder; – wet massing with molten binder; – extrusion into a spaghetti-like extrudate; – spheronization from the extrudate to spheroids of

uniform size; – sifting to achieve the desired size distribution

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Melt extrusion/extrusion spheronization

• Melt extrusion is a solvent free process that allows high drug loading as well as content uniformity for low dose high potency actives.

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In vitro dissolution• Unlike conventional dosage forms, from which the drug

substance simply dissolves in the aqueous dissolution test media, lipid-based formulations release the drug from an oily solution which is often immiscible with water.

• In evaluating drug release from a lipid-based formulation, quantification of the surface area of the dispersed oil droplets is deemed more critical in assessing formulation performance than is solubilization of drug in the aqueous test media which, if it occurs at all, is unlikely to be

reflective of in vivo formulation performance.

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In vitro dissolution• There are no standard pharmacopoeial methods for

testing lipid-based formulations.

• Release and absorption of drugs from oily dispersions in vivo is thought to occur subsequent to lipid digestion and micellization or possibly, via direct transfer from the oil droplets to the intestinal epithelia, the efficiency of both processes being proportional to the total oil droplet surface area.

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In vitro dissolution• In the case of formulations which incorporate large

amounts of surfactant (e.g., self-emulsifying formulations), evaluation of the oil droplet size formed in a biorelevant aqueous test medium could prove of value in anticipating drug release in vivo.

• However, in instances where the formulation depends on gastrointestinal processing for emulsification (e.g., a simple oily solution of drug), design of a meaningful release test will require evaluation of drug release from the formulation in the presence of lipolytic enzymes that

catalyze GI lipid digestion in vivo.

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In vitro dissolution• Dispersion testing, i.e. emulsification capacity and

analysis of particle size distribution is often used to assess the effectiveness of self-emulsifying formulations.

• Emulsification capacity is generally evaluated visually and particle size distribution can be measured either by optical microscopy, laser light diffraction or Photon Correlation Spectroscopy (PCS) depending on the fineness of the dispersion.

• Dispersion testing is vital for Type III and Type IV formulations, which may lose solvent capacity on dispersion due to migration of water-soluble components into the bulk aqueous phase

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In vitro dissolution• Digestion testing is of even greater significance because

it offers the opportunity to predict the fate of the formulation and drug in the intestinal lumen prior to absorption.

• Digestion tests are essential for evaluation of Type I, Type II, and Type III formulations, and given that surfactants are subject to digestion, probably for Type IV formulations as well.