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Poloxamers

What is a Poloxamer?

Poloxamers are also known as polyethylene- propylene glycol copolymer or polyoxvethylene-polyoxypropylene copolymer. They are a series of block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).

All poloxamers are chemically similar in composition, differing only in the relative amounts of propylene and ethylene oxides added during manufacture. The presence of PEO and PPO blocks in a single polymer chain imparts to the molecule amphiphilic properties whose self-assembling properties display a wide range of phase behaviour.

Several different types of poloxamers are commercially available whose physical and surface-active properties vary over a wide range. Pharmacopoeial grades generally occur as white, waxy, granules or as solids. They are practically odourless and tasteless.

Poloxamers are listed in pharmacopoeia and generally regarded as nontoxic and non-irritant. Included in the FDA Inactive Ingredients Database (IV injections; inhalations, ophthalmic preparations; oral powders. solutions, suspensions, and syrups; topical preparations).

The general chemical structure of Poloxamers is shown below:

Generalised Chemical Structure of Poloxamer

Chemical Name Poloxamer
CAS Registration Number [9003-11-6]
Empirical Formula HO(C2H4O)a(C3H6O)b(C2H4O)aH
Molecular weight 2090 – 14 600 (average)
Regulatory Status PhEur; USP-NF; JPE
Poloxamer type Ethylene oxide units (a) Polypylene oxide units (b) Content of oxyethylene (%) Average molar mass
124 10 – 15 18 – 23 44.8 – 48.6 2090 – 2360
188 75 – 85 25 – 30 79.9 – 83.7 7680 – 9510
237 60 – 68 35 – 40 70.5 – 74.3 8740 – 8830
338 137 – 146 42 – 47 81.4 – 84.9 12700 – 17400
407 95 to 105 54 to 60 71.5 to 74.9 9840 to 14 600

Key Physicochemical Properties of Poloxamers

Acidity/aikalinity pH = 5.0—7.4 for a 2.5% w/v aqueous solution
Cloud point > 100C for a 1% w/s aqueous solution, and a 10% w/v aqueous solution of poloxamer 188
HLB value 0.5 – 30
Melting Point 16oC for poloxamer 124; 52 – 57oC for poloxamer 188; 49oC for poloxamer 237; 57oC for poloxamer 338 and 52-57 oC for poloxamer 407
Solubilitiy Solubility varies according to the poloxamer type
Surface tension 19.8 mN/m for a 0.1% w/v aqueous poloxamer 188 solution at 25C; 24.0mN/m for a 0.01% w/w aqueous poloxamer 188 solution at 25C; 26.0 mN/m for a 0.001% w/v aqueous poloxamer solution at 25 C
Viscosity (dynamic) 1000 mPas as a melt at 77C for poloxamer 188

 

How are Poloxamers Used in Formulations?

The main uses of poloxamers is as dispersing agents, emulsifying agents, solubilizing agents, tablet lubricants, wetting agents and foaming agents.

As nonionic polyoxyethylene-polyoxypropylene copolymers, poloxamers are used as emulsifying or solubilizing agents. They are used as emulsifying agents in intravenous fat emulsions and as solubilizing and stabilizing agents to maintain clarity of elixirs and syrups.

Poloxamers can also be used as wetting agents; in ointments, suppository bases, and gels; and in tablet binders and coatings. Poloxamer 188 has also been used as an emulsifying agent for fluorocarbons used as artificial blood substitutes, and in the preparation of solid-dispersion systems. More recently, poloxamers have found use in drug-delivery systems.

Therapeutically, poloxamer 188 is administered orally as a wetting agent and stool lubricant in the treatment of constipation; it is usually used in combination with a laxative such as dantron. Poloxamers may also be used therapeutically as wetting agents in eye-drop formulations, in the treatment of kidney stones, and as skin-wound cleansers.

 

Any Useful Tips?

Naming of poloxamers can be bewildering but typically, the nonproprietary name – poloxamer – is followed by a number: the first two digits of which, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer and the third digit, when multiplied by 100, corresponds to the percentage by weight of the polyoxyethylene portion.

Similarly, with many of the trade names used for poloxamers e.g. Kolliphor 188, the first digit arbitrarily represents the molecular weight of the polyoxypropylene portion and the second digit represents the weight percent of the oxyethylene portion. The letters L, ‘P’, and ‘F’, stand for the physical form of the poloxamer: liquid, paste, or flakes.

Although the USP-NF contains specifications for five poloxamer grades, many more different poloxamers are commercially available that vary in their molecular weight and the proportion of oxyethylene present in the polymer.

Some poloxamers (e.g Poloxamer 188) are incompatible with parabens.

Poloxamers are used in the cosmetics field as oil-in-water emulsifiers, cleansers for mild facial products, and dispersing agents.

References

[1] R.G. Strickley, Solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, 21 (2004) 201-230.

[2] G. Dumortier, J.L. Grossiord, F. Agnely, J.C. Chaumeil, A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics, Pharmaceutical Research, 23 (2006) 2709-2728.

[3] A.M. Bodratti, P. Alexandridis, Formulation of Poloxamers for Drug Delivery, Journal of Functional Biomaterials, 9 (2018).

 

Gellan Gum

What is Gellan Gum?

Gellan gum is a water soluble anionic hydrocolloid produced by the microorganism Sphingomonas elodea. This microorganism was discovered in 1978 in the United States by scientists at Merck following a concerted effort to find naturally occurring hydrocolloids.

Gellan gum is supplied as a free-flowing white powder. For commercial grades, gellan gum is manufactured by fermentation of a carbohydrate. In its native state, Gellan gum has acyl groups in its structure. Treatment with alkali removes acyl groups completely

Physicochemical Properties of Gellan Gum

Chemical Structure

Gellan gum is a straight chain polymer consisting of D-glucose, L-rhamnose and D-glucuronic acid units. In its native or high acyl grade, acetate and glycerate substituents are present on one of the glucose residues. The low acyl grade there is no acyl substituents. Note that the presence of acyl groups has a strong bearing on gel properties of Gellan gum.
Gellan Gum

Differences between High Acyl and Low Acyl Gellan Gum

  High Acyl Gellan Gum (KELCOGEL® LT100 Low Acyl Gellan Gum
Molecular weight 1 – 2 x106 Daltons 2 – 3 x105 Daltons
Solubility Hot water Cold or hot water
Set Temperature (oC) 70 – 80 30 – 50
Thermoreversibility Thermoreversible Heat stable

Where can you use Gellan gum?

Gellan gum is a useful and effective gelling agent in pharmaceutical and food products. It offers the following benefits:

  • It is effective at low concentrations
  • Provides a wide range of viscosities and textures
  • Gels on cooling
  • Forms fluid gels, which are solutions with a weak gel structure. These systems are extremely versatile for suspending drug substances without settling
  • Can be used in combination with other hydrocolloids

Uses of Gellan gum in pharmaceutical products

Application Typical products
Oral suspensions (immediate and sustained release) Ibuprofen, Paracetamol, Cetirizine
In-situ forming gels Nasal and ophthalmic products
Medicated gummies Vitamins and children medicines
Hair care products Stabilization of medicated shampoo formulations
Topical products Creams and lotions as a substitute for paraffins
Tablet coatings To improve slip and enhance swallowing
Oral care In toothpaste formulations to bind actives while creating a gel-like texture

Regulatory status

Approved for use in foods in Europe, USA, Japan, China and India. Gellan gum is also approved for use in non-food, cosmetics and pharmaceutical formulations in the USA, Canada, Australia, Brazil and China. Pharmaceutical use in EU falls under E418 (Directive EC/95/2). Gellan gum is manufactured in accordance with applicable food GMPs and complies with purity criteria defined in the current USP-NF monograph.

References

KELCOGEL® Gellan gum book, 5th Edition, CP Kelco, San Diego, USA

Mahdi M H et al., 2014. Evaluation of Gellan gum fluid gels as modified reléase oral liquids. International Journal of Pharmaceutics, 475; 335 – 343.

Kubo W et al., 2003. Oral sustained delivery of paracetamol from in-situ gelling Gellan and sodium alginate formulations. International Journal of Pharmaceutics, 258 (1-2); 335 – 343; 55-64

 

 

 

AEROPERL® 300 Pharma Mesoporous Silica

What is AEROPERL® 300 Pharma Mesoporous Silica?

AEROPERL® 300 Pharma is a mesoporous silica obtained by granulating colloidal silicon dioxide. Mesoporous silicas are of great interest in the pharmaceutical industry due to their unique properties, such as ordered pore structures, very high internal surface areas and availability in a variety of shapes and morphologies (spheres, rods and powders).

Scanning electron micrograph of AEROPERL® 300 Pharma

Physicochemical Properties AEROPERL® 300 Pharma Mesoporous Silica

Specific surface area (BET) m2/g 260 – 320
pH 3.5 – 5.5
Tapped density (g/l) ≈270
Average particle size (µ) 26 – 60
Pore volume (ml/g) 1.5 – 1.9
Shape Speherical

How is AEROPERL® 300 Pharma Mesoporous Silica used in Formulations?

Improving the Bioavailability of Poorly Water Soluble Drug Molecules

For poorly soluble active pharmaceutical ingredients (BCS II and IV) increasing the effective surface area in contact with the dissolution medium can enhance the rate of drug dissolution and improve bioavailability. This can be achieved by loading the drug substance in the form of small crystallites onto AEROPERL® 300 Pharma surface. Alternatively, the drug substance can be dissolved into a lipid carrier which is then adsorbed onto the mesoporous silica surface. Both these approaches result into a homogeneous and reproducible drug-loading and release.

Conversion of Liquid Lipid Formulations into Powders

Owing to its porous and highly adsorptive properties, AEROPERL® 300 Pharma can be used to change lipid formulations into powders. It is possible to use the material as a carrier and load it with up to 150% of its own weight with an oil without compromising its powder flow properties. This is undertaken via a simple blending process without the need for specialised equipment.

The high capillary forces draw the liquid into the pores. Moreover, this is a purely physical phenomenon, meaning that polarity of the lipid does not impact on adsorption – so provided the oil has reasonable viscosity, it will be adsorbed.

Inorganic Solid Dispersions via Solvent Evaporation Technique

AEROPERL® 300 Pharma has been investigated as an inorganic dispersion material for poorly soluble active pharmaceutical ingredients (API) in order to increase their dissolution rates. The API is first dispersed in a suitable solvent such as acetone, which is then added to AEROPERL® 300 Pharma. The acetone is then evaporated off resulting into adsorption of the API onto the surface of the mesoporous silica.

Enzyme Encapsulation into Mesoporous Silica for Biocatalysis

Owing to their pore size, pore structure and particle morphology mesoporous silica materials are of interest to many applications requiring enzymes to be immobilized or supported in situ. Immobilization of enzymes can result in enhanced stability, ease recovery and re-use, and allow the enzyme to be used in non-aqueous solvents where the enzyme is insoluble.

AEROPERL® 300 Pharma is ideally suited as a support material due to it mechanical and chemical stability as well as high surface area. It is also comparatively low cost and exhibits low non-specific protein adsorption properties. This means that adsorption of the enzyme is least likely to compromise the enzyme conformation or activity.

Moisture Activated Dry Granulation (MADG)

MADG is an approach to granulation carried out in a high shear granulator similar to conventional wet granulation except that the amount of water used is limited and there is no heat-based drying step. MADG starts with the addition of small quantities of water to a powder mix comprising the active ingredient(s), binder and other excipients, which is then blended under high shear to achieve agglomeration. The mesoporous silica, as the moisture absorbing excipient, is then added to the mixture to absorb excess moisture and to ‘dry’ the granules.

AEROPERL® 300 Pharma mesoporus silica offers an innovative approach to wet granulation processing. Studies have shown that AEROPERL® 300 Pharma serves as an efficient moisture absorber due to its high surface area and pore volume. The added moisture is bound effectively to create a stable, functional dry granular powder that can be readily processed via tabletting, capsule filling or dosing into sachets.

References

Ahern, R.J.; Hanrahan, J.P.; Tobin, J.M.: Ryan, K. B.; ,Crean, A.M.; European Journal of Pharmaceutical Sciences, 2013 50 400

Abdallah, N.H.; Schlumpberger, M.; Gaffney, D.A.; Hanrahan, J.P.; Tobin, J.M.; Magner, E.M.; J. Mol. Cat B: Enzymatic, 2014 108 82

Benzalkonium Chloride

What is Benzalkonium Chloride?

Benzalkonium chloride, also known as BKC, BAK or Alkyl dimethyl benzyl ammonium chloride, is a quaternary ammonium salt and a cationic surfactant with broad antimicrobial activity against bacterial, yeasts, fungi and viruses. It is a mixture of alkybenzydimethylammonium chloride, the alkly groups having lengths of 8 to 18. The general chemical structure of Benzalkonium chloride is shown below:


n = 8, 10, 12, 14, 16, 18

Chemical Name Alkyldimethyl (phenylmethyl)ammonium chloride
CAS Registry Number [8001-54-5]
Molecular Weight 354 – 360.
Regulatory Status PhEur; USP-NF

Physicochemical Properties of Benzalkonium Chloride

Physical form

White or yellowish-white powder, gel or gelatinous flakes
Acidity/alkalinity pH 5-8 (10% w/v aqueous solution)
Melting point 40 oC
Partition coefficients The octanol; water partition coefficient varies with the alkyl chain length of the homolog: 9.98 for C12, 32.9 for C14 and 82.5 for C16.
Solubility Very soluble in water and ethanol. Aqueous solutions foam when shaken, have a low surface tension and possess detergent and emulsifying properties.

How is Benzalkonium Chloride Used in Formulations?

Benzalkonium chloride is widely used in inhalations, IM injections, nasal, ophthalmic, and topical preparations as an antimicrobial preservative, antiseptic, disinfectant, solubilizing and wetting agent. It is used in similarly to other cationic surfactants, such as cetrimide.

In ophthalmic preparations, benzalkonium chloride is the preservative of choice and one of the most widely used preservatives, at concentrations of 0.01-0.02% w/v.

Antimicrobial activity can be enhanced, particularly against strains of Pseudomonas, benzalkonium chloride, through combination with other preservatives or excipients, such as 0.1% w/v Disodium edetate, phenylethanol or chlorhexidine.

In nasal formulations, benzalkonium chloride is used at a concentration of 0.002-0.02% w/v. Levels of 0.01% w/v have also been utilized in small-volume parenteral products.

Benzalkonium chloride can also be added to topical medical devices, antiseptic wipes and cosmetics as an alternative to parabens. It produces significantly less stinging or burning compared with isopropyl alcohol and hydrogen peroxide when used in topical products.

 

Any Comments and Useful Tips?

Benzalkonium chloride solutions are active against a wide range of bacteria, yeasts, and fungi. Activity is more marked against Gram-positive than Gram- negative bacteria but minimal against bacterial endospores and acid-fast bacteria. The antimicrobial activity of Benzalkonium Chloride is greatly dependent on the alkyl composition of the mixture.

Note that benzalkonium chloride has been associated with ototoxicity when applied to the ear. Prolonged contact with the skin may cause irritation and hypersensitivity. Benzalkonium Chloride is also known to cause bronchoconstriction in some asthmatics when used in nebulizer solutions.

Benzalkonium chloride is not suitable for use as a preservative in solutions used for storing and washing hydrophilic soft contact lenses, as the Benzalkonium Chloride can bind to the lenses and may later produce ocular toxicity when the lenses are worn.

Local irritation of the throat, oesophagus, stomach, and intestine can occur following contact with strong solutions (>0.1% w/v).

 

References

[1] F.G. Casablancas, Novo Nordisk Pharmatech A/S.

[2] H.S. Bean, Preservatives for pharmaceuticals, J. Soc. Cosmet. Chem, 23 (1972) 703-720.

[3] B.B. Tarbox., et al., Benzalkonium chloride. A potential disinfecting irrigation solution for orthopaedic wounds, Clinical orthopaedics and related research, (1998) 255-261.

[4] C. Boukarim, S. Abou Jaoude, R. Bahnam, R. Barada, S. Kyriacos, Preservatives in liquid pharmaceutical preparations, J Appl Res, 9 (2009) 14-17.

Formulating

Hypromellose vs Polyethylene Oxide in the Formulation Matrix “Mini” Tablet Systems

Abstract

In this study, a novel ‘mini tablet’ matrix system was developed using hypromellose and polyethylene oxide to determine if it resolved the commonly faced issue of dose dumping in monolithic systems. Using theophylline as the model drug, dissolution profiles of the matrix mini tablets were obtained with the aid of a USP apparatus 1 and 4 The results indicate two-compartment mini-tablets exhibited slower drug-release as well as an absence of the initial rapid drug-release seen in one-compartment systems. Of the polymer combinations tested, polyethylene oxide (as the internal polymer) and hypromellose (as the external polymer) combination showed the highest potential for resisting dose-dumping when agitation was increased (showing only an increase of 4.1% in drug-release, in comparison to a 42.5% increase shown by a commercially theophylline product, Uniphyllin®), This study shows that the concept of a matrix mini tablet system is a promising option for preventing dose-dumping although further work is required to optimise the system.

 

Background to the study

The need for frequent oral administration in cases of chronic disease can deter patients’ compliance to medication. While prolonged drug-release formulations can reduce dosing frequency and support better patient compliance and outcomes (Augsburger and Hoag, 2008), the incorporation of large drug concentrations in a single dosage form poses a potential risk to patient’s a health should drug-release characteristics of the dosage form become affected, for instance, when the phenomenon of ‘dose-dumping’ occurs (Mayer and Hussain, 2005).

Dose dumping may be induced by several factors; the commonest ones being consumption of meals before ingestion of medication (Hendeles et al., 1985; Karim et al., 1985, Schmidt and Dalhoff, 2002). Hendeles et al.(1985) found that consumption of a breakfast of bacon and eggs prior to administration of theophylline sustained-release formulations induced dose-dumping. Dose dumping was attributed to exposure to the alkaline bile salts or pancreatic enzymes following postprandial gastric emptying.

Hydrophilic diffusion-based monolithic matrix systems are a popular sustained-release system due to their enhanced reliability, relatively cheap manufacturing cost and ease of formulation (Augsburger and Hoag, 2008). The drug is dispersed evenly in a polymer and upon contact with GI tract fluids, a gel-layer forms to serve as a barrier to fluid movement into and drug movement out of the system. Commonly used polymers for hydrophilic matrices include hypromellose, polyethylene oxide and methacrylic acid copolymers (Tiwari and Rajabi-Siahboomi, 2008, Appicella et al., 1993).

A flaw in the design of monolithic matrix systems is that when conditions promoting rapid drug-dissolution are encountered in vivo, a high proportion of the drug is immediately released into the gastrointestinal (GI) tract, potentially exposing the individual to a high dose (Hendeles et al., 1985). Previous attempts at modulating this initial burst of drug-release have been unsuccessful (Samuelov et al., 1979; Cobby, 1974; Conte (1993).

Novel ‘mini-tablet’ matrix systems, consisting of two-compartments, have been developed in an attempt to modulate drug release and to resolve the consequences of tablet rupture (De Brabander et al., 2000; Efentakis et al., 2000; Lopes et al., 2007). In this context, the two compartments are the mini-matrix tablet domain (internal) surrounded by a continuous polymer formulation (external). The containment of the drug within these internal polymer domains leads to an additional barrier separating the drug from GI fluid, thus preventing the immediate dumping of large quantities of drug. This is shown in figure 1 below.

Conceptualisation of the mini-tablet system. Grey area is the external polymer domain; the yellow area is the internal domain polymer and the blue dots represent the drugFigure 1: Conceptualisation of the mini-tablet system. Grey area is the external polymer domain; the yellow area is the internal domain polymer and the blue dots represent the drug

Objectives of the study

The objectives of the study were to determine the dissolution profiles of four different combinations of theophylline mini-tablets and to assess the suitability of PEO and HPMC as polymers for the internal and external domains of mini-tablets. Drug release profiles were investigated with the aid of the USP Apparatus 1 and 4 were used, with Hanks buffer at pH 7.4 used as the dissolution media. The vessels containing the media were sealed when possible throughout the investigation to prevent the escape of CO2.

Study Methodology

Materials

Theophylline anhydrous was purchased from Sigma Aldrich, UK, Hypromellose (Methocel™ K100M and Polyethylene Oxide (Polyox ™ WSR 1105) were kindly donated by Colorcon UK, Lactose anhydrous was gifted by Kerry Group, Dublin, Ireland, Colloidal Silica (HDK® N20 Pharma) was kindly provided by Wacker AG and Microcystalline Cellulose was purchased from Sigma ALdrich UK. The rest of the materials were technical grade materials purchased from a variety of vendors.

 

Methods

Preparation of Matrix ‘Mini Tablets’

Mini matrix tablets (total batch size of 400g) were prepared according to the scheme in table 1 and formulas in table 2 below.

 

Table 1:- The four combinations of the mini-tablet formulations evaluated

 

Internal mini-tablet polymer External polymer Tags
PEO HPMC P/H
PEO PEO P/P
HPMC Hypromellose H/H
HPMC PEO H/P

Table 2: Formulations used to produce mini-tablets

 

Ingredient % (w/W Quantity g (for 400g)
Theopylline 20.0 80
PEO/Hypromellose 20.0 80
MCC 15.0 60
Lactose 44.3 177.2
7-hydroxycoumarin 0.1 0.4
Magnesium Stearate 0.5 2
Colloidal silica 0.1 0.4

 

In each case, hypromellose or polyethylene oxide was blended with theophylline, microcrystalline cellulose and lactose for 5minutes. Magnesium stearate was then added and blending continued for a further 3 minutes. Finally, the 7-hydroxycumarin and colloidal silica were added and blending undertaken for a further 3 minutes.

All powder blends were assessed for flowability (Carr’s compressibility index and angle of repose). Tablet compression was undertaken on Riva Minipress Single Punch tablet press using 2 mm tooling. The obtained mini matrix tablets were then manually dosed into a 15 mm dies to which a portion of the appropriate external polymer blend had been added and compressed to create the mini matrix tablet system. Each system was designed to contain 50mg of theophylline.

Friability, hardness testing, and uniformity of weight of the macro tablets were performed using an ErwekaTA-120 friabilator and Erweka TBH-220D hardness machine.

 

Dissolution testing

USP Apparatus 1 dissolution testing at 100rpm

An Erweka DT 600A USP Apparatus 1 machine set to either 100rpm or 150 rpm (bath temperature 37°C) was used. 1L of Hanks buffer (pH 7.4) was placed in each vessel. At intervals of 0.5, 1, 2, 3, 4, 5, 6 and 26 hours, samples were withdrawn and absorbances taken using an Agilent UV spectrophotometer set at 268nm. The withdrawn aliquots were replaced with an equal amount of fresh dissolution media at the same temperature.

 

USP Apparatus 4: dissolution testing

A Sotax CE7 Smart USP Apparatus 4 was set to a temperature of 37°C and flow rate of 8 ml/min. One 5mm ruby bead was placed at the bottom of each of the 7 Dissotest cells and covered with 1mm glass beads up to one third of the cell. The tablets were placed into cells and Hanks buffer (pH 7.4) used as the test media. Readings were automatically taken at 30minute intervals for 15 hours. Measurements were performed in triplicate.

 

Results

Mini Tablets Characteristics

Lower compressibility and angle of repose values were obtained for the PEO powder compared with hypromellose suggesting that the PEO powder had better flow and tableting properties. Both powders produced tablets which had the weight and friability values consistent with current British Pharmacopoeia requirements (see table 3).

Table 3: Test results on macro tablets used to make the micro-domains

 

PEO Hypromellose
Powder flowability
Compressibility (%) 16.0 % 24.0 %
Angle of repose 36° 43°
Weight:
Mean 0.346g 0.349g
Standard deviation 0.002006 0.002102
Friability (%) 0.186 % 0.178%
Hardness:
Mean 96.1 ± 0.3 N 88.5 ± 0.4 N

Dissolution Tests

Drug release profile of the matrix systems are shown in Figure 2 to 4. Figure 2 and 3, which pertain to USP Apparatus 1 tests reveal faster drug-release in monolithic matrix tablets compared with the the two-compartment systems. The former also exhibit an initial rapid release of drug within the first 30 minutes. Increasing agitation (100 to 150 rpm) resulted in increase in drug-release. Systems formulated with PEO alone showed the fastest overall drug release profile. This was followed by commercial theophylline product.

The patterns of drug release for mini matrix tablet systems were clearly different from monolithic tablets. Moreover, there were differences between the different polymers with respect to what was added to the external versus internal phases. Finally, the two-compartment systems achieved more prolonged release and also avoided the initial spike in release, a result that is in agreement with what O’Connor (2011) reported.

Dissolution profiles of the 6 dosage forms using USP apparatus 1 at 100rpm

Figure 2: Dissolution profiles of the 6 dosage forms using USP apparatus 1 at 100rpm

Dissolution profiles of the 6 dosage forms using USP apparatus 1 at 150rpmFigure 3: Dissolution profiles of the 6 dosage forms using USP apparatus 1 at 150rpm

Cumulative percentage drug-release of 4 dosage forms using USP Apparatus 4Figure 4 shows the drug release profiles of the matrix systems as obtained from the USP Apparatus 4. The two-compartment matrix systems achieved more prolonged release while avoiding the initial spike in release. The PEO macro tablet had the fastest drug-release rate, followed initially by the commercial tablet. H/P, H/H and P/H systems, too, showed readings only from 1.5 hours. However P/H and H/H did not appear to release drug loads.

 

 

Figure 4: Cumulative percentage drug-release of 4 dosage forms using USP Apparatus 4

 

Discussion

The absence of the initial spike in drug-release with minitablets may be due to the lack of drug closer to dosage-form surface as the drug is contained within the internal domains. The distance presents a longer path for both the media and the drug travel, which slows down the diffusion and release of the drug substance. In monolithic matrices, if conditions present that promote drug to be released, there is an increased likelihood of reaching toxic-levels in these systems.

A direct comparison between P/P and the macro tablets highlight the difference in drug-release between one- and two-compartment models. Both used identical polymers yet had very different release profiles. The macro tablet released 50% of its dose in just 1.4 hours (at 100rpm) and 1.0 hours (at 150rpm) compared to the 9.5 hours (100rpm) and 5.9 hours (150rpm) of P/P, respectively representing a 7- and 6-fold increase in the time taken for the two-compartment model.

USP 4 data suggest the drug release characteristics of P/P system are unsuitable due to the rapid rate of drug release, which is even faster than the commercial tablets. This suggests that P/P systems are more prone to dose-dumping. H/H and P/H are also unsuitable as drug-release was extremely low and hence impractical for reaching the required therapeutic drug levels.

 

Effect of increasing agitation

The robustness of the formulations appears unrelated to whether the dosage forms were of a one- or two-compartment design. The greatest effect on drug release when rotation in USP 1 was increased from 100rpm to 150 rpm was seen on P/P where it showed to be 61% faster for the first 50% release of drug. H/P showed the second largest increase, followed by the commercial tablet at 42.5%, the macro tablet at 35.6%, and P/H at 4.1%. These results suggest presence of the internal domains alone is not enough to assume higher resistance to dose-dumping. Properties of the polymers within the dosage-form must also be considered. An investigation by Maggi et al. (2000) found the PEO gel-layer to be weaker and less-effective in preventing water-entry than the hypromellose gel-layer, resulting in an increased rate of gel-erosion and drug-release.

Figure 5 shows the result of an experiment where pure PEO and HPMC tablets were submerged in water. The presence of undissolved solids at 20 hours within the HPMC tablet system is indicative of hypromellose higher resistance to water entry into the tablet compared to PEO which showed no signs of undissolved polymer from 15hrs onwards. Additionally the greater diameter of the hypromellose tablet after 20 hours indicates the higher strength of its gel-layer.

 

Figure 5: Dissolution profile of tablets made of pure PEO (left) and HPMC (right) at 8hrs (top) 15hrs (middle) and 20hrs (bottom) (from from Maggi et al., 2000)

Figure 5: Dissolution profile of tablets made of pure PEO (left) and HPMC (right) at 8hrs (top) 15hrs (middle) and 20hrs (bottom) (from from Maggi et al., 2000)

 

Effect of internal and external domains on drug-release

H/P and P/H despite containing both hypromellose and PEO displayed very different drug-release and stability properties. This suggests that the influence of the polymer in the internal domain versus the external domain on drug-release is unequal. Performance at 100rpm of the two systems was selectively compared with P/P. H/P drug-release was only 24.6% less than P/P while P/H drug-release was 56.9% less, more effectively expressing the slower drug-releasing properties of HPMC. This suggests the polymer in the external domain influences drug-release more than the internal domain in two-compartment systems. These results coincide with observations made by Maggi et al. (2000) who found the external layers play the major role in controlling drug release.

 

Conclusions

PEO and Hypromellose, whether alone or in combination cannot achieve a suitably strong dosage form with good drug-release properties. P/H was the only formulation to show similar drug-release profiles for 100rpm and 150rpm. This may be an indication that this formulation is robust and is unlikely to dose dump. Further optimization is suggested, including the use of lower viscosity grades of hypromellose in the P/H formulation to tailor drug-release while maintaining resistance to erosion. Varying the external polymer as the internal domains appears to have less effect on the drug-release properties of the dosage-form and so should be kept constant.

 

References

Apicella, A. Cappello, B. Del Nobile, M. La Rotonda, M. Mensitieri, G. Nicholais, L. (1993). Poly (ethylene oxide) (PEO) and different molecular weight PEO blends monolithic devices for drug release. Biomaterials. 14 (2), 83-90.

Augsburger, L. and Hoag, S., 2008. Pharmaceutical Dosage Forms: Tablets. 3rd ed. Vol. 2: Rational Design and Formulation. Informa Healthcare USA, Inc.

De Brabander C, Vervaet C, Görtz JP, Remon JP, Berlo JA. Bioavailability of ibuprofen from matrix mini-tablets based on a mixture of starch and microcrystalline wax. Int J Pharm. 2000 Nov 4;208(1-2):81-6. doi: 10.1016/s0378-5173(00)00549-4. PMID: 11203270.

Cobby, J. Mayersohn, M. Walker, G. (1974). Influence of Shape Factors on Kinetics of Drug Release from Matrix Tablets. Journal of Pharmaceutical Sciences. 63 (5), 732-737.

Conte, U. Maggi, L. Colombo, P. La Manna, A. (1993). Multi-layered hydrophilic matrices as constant release devices ( GeomatrixTM Systems*). Journal of Controlled Release. 26, 39-47.

Efentakis M, Koutlis A, Vlachou M. Development and evaluation of oral multiple-unit and single-unit hydrophilic controlled-release systems. AAPS PharmSciTech. 2000;1(4):E34. Published 2000 Dec 1. doi:10.1208/pt010434

Hendeles, L. Weinberger, M. Milavetz, G. Hill, M. Vaughan, L. (1985). Food-induced “dose-dumping” from a once-a-day theophylline product as a cause of theophylline toxicity. Official publication of the American College of Chest Physicians. 87 (6), 758-765.

Karim, A. Burns, T. Wearley, L. Streicher, J. Palmer, M. (1985). Food-induced changes in theophylline absorption from controlled-release formulations. Part I. Substantial increased and decreased absorption with Uniphyl tablets and Theo-Dur Sprinkle. Clin Pharmacol Ther. 38, 77-83.

Lopes, C M, Lobo J M, Pinto J F, Costa P C. Compressed matrix core tablet as a quick/slow dual-component delivery system containing ibuprofen. AAPS PharmSciTech. 2007 Sep 21;8(3):E76. doi: 10.1208/pt0803076. PMID: 17915826; PMCID: PMC2750572.

Maggi, L. Bruni, R. Conte, U. (2000). High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage forms. International Journal of Pharmaceutics. 195, 229-238.

Meyer, RJ. Hussain, AS. (2005). Mitigating the Risks of Ethanol Induced Dose Dumping from Oral Sustained/Controlled Release Dosage Forms.Center for Drug Evaluation and Research. 1, 1-4.

Samuelov, Y. Dunbrow, M. Friedman, D. (1979). Sustained release of drugs from Ethylcellulose-polyethylene glycol films and kinetics of drug release. Journal of Pharmaceutical Sciences. 68, 325-329.

Schmidt, L. Dalhoff, K. (2002). Food-Drug Interactions. Drugs. 62 (10), 1481-1502.

 


Hypromellose vs Polyethylene Oxide in the Formulation Matrix “Mini” Tablet Systems

B Hussain and J Simon

Pharmacentral Laboratory

Faculty of Science and Technology, University of Central Lancashire, Preston, PR1 2HE

Formulating

A Fail-Safe Guide to Taste Masking Oral Products with Ion Exchange Resins

What are Ion Exchange Resins?

Ion Exchange Resins (IER) are synthetic pharmacopoeia grade water insoluble cross-linked polymers that contain a salt-forming group at regular positions on the polymer chain and have the capacity to exchange counter-ions in aqueous solution.

IERs were developed in the 1930s for water purifications applications. In the 1950s, they were introduced in the pharmaceutical industry as APIs and excipients. Currently, IERs are varyingly utilised as pharmaceutical excipients for controlling drug release agents (matrix tablets), solubility enhancement, increasing stability, taste masking and abuse deterrents.

Although there are many grades of IERs, only two materials currently meet official compendial requirements and are widely recommended for use in products. These are Polacrilin Potassium NF and Sodium Polystyrene Sulfonate USP-NF.

 

Selection and Grades of IERs

Polacrilin Potassium NF Sodium Polystyrene Sulfonate USP
Chemical Description Potassium salt of a cross-linked copolymer of methacrylic acid and divinylbenzene Sodium salt of a sulfonated copolymer of styrene and divinylbenzene
Physical Form White, fine or granular powder White, fine powder
Pharmacopoeia USP-NF USP-NF
Solubility Insoluble Insoluble
Hygroscopicity Hygroscopic Hygroscopic
Type Weak acid Strong acid
Functional Group -COO- -SO3
Exchangeable Cation Potassium Sodium
pH Dependence Yes No
Commercial Grades AMBERLITE™ IRP88 (Dow)

KYRON T-134 (Corel Pharma)

AMBERLITE™ IRP69 (Dow)

KYRON T-154 (Corel Pharma)

 

Advantages of IERs

  • IERs are highly versatile – they can be used in most oral drug delivery systems, including ODTs, tablets, chewable and effervescent tablet, capsules as well as dry syrups and liquid suspensions.
  • IERs can significantly improve safety and patient adherence by helping mask bitter tastes, improve bioavailability and reduce pill burden
  • IERs have a long history of use – spanning over 50 years of safety data.
  • IERs are simple to use – they do not require major changes to equipment or processes.

 

How to use IERs for Taste Masking

IERs provide an effective means to bind the bitter active principle onto an insoluble matrix via a simple ion exchange reaction. The reaction is a reversible, selective and stoichiometric exchange of ionic species that have similar charges.

The wet taste-masked complex can be used for suspension formulation directly. Alternatively, it can be dried and used in tablet, capsule or dry syrups.

The process of using IER for taste masking could not be any easier. There are two main ways to load the drug (API) on to the EIR: column method and batch method. The column method involves passing a highly concentrated solution of the API through a column of resin particles until equilibrium complexation is achieved. The batch process involves agitating a solution of the drug with a quantity of the IER until equilibrium complexation is achieved.

Generally, the batch method is preferred as it is simple and straightforward. A predetermined amount of drug is loaded onto the IER, the quantity added mainly influenced by the cation exchange capacity (which is a measure of an IER’s ability to hold exchangeable cations and therefore bind the API). The other factors that influence loading are the IER’s selectivity for the API, particle size, porosity and degree of crosslinks.

To start, it is important to identify the most ideal IER for the API. If not sure, consult your supplier for guidance. However, a simple screening process can be done that involves preparation of 1% w/v API solution to which the IER is added in different ratios, e.g 1:1, 1:2, 1:3, etc. The blends are stirred for up to 20 hours and sample solutions taken at regular interval in order to assay for free, uncomplexed drug. The most suitable IER is then one with the lowest amount of free drug (concentration remaining in solution).

The process is illustrated below:

Once the equilibration is completed, the IER-API complex can be washed, and used as is in syrups and suspensions or dried and blended with other excipients and compressed into tablets of choice or filled into capsules.

 

Usability Rating

References

Martel, J. J et al., 1981. Acid type ion Exchange resins and their use as medicines and compositions containing them. Patent EP27768.

Felton, L. A., 2018. Use of polymers for taste-masking pediatric drug products. Drug Devt Ind. Pharm 44, 1049 – 1055.

 

Carbomers: Overview, Key Properties and Formulating Tips

Carbomers are an important group of excipients that every well-meaning formulator should become familiar with. Here is a quick run-through of what they are, uses and formulation tips.

Carbomers: Overview, key properties and formulating tips

Chemistry and Physical Description

Carbomers are synthetic, chemically related, high molecular weight, nonlinear polymers based on crosslinked acrylic acid chemistry.

Originally developed by BF Goodrich and trademarked CARBOPOL® in 1958. These materials (especially, Carbopol 940, 941, and 934) revolutionised topical products by enabling formulators to create new types of product previously not possible.

The general chemical structure of carbomers is shown below:

Key Physicochemical Properties

  • Molecular weight 700 kDa to 4 000 000 kDa
  • Hygroscopic
  • Powdered carbomers have a dry particle agglomerated size of 2-7µm.
  • Do not dissolve but swell in ethanol, water, propylene glycol and glycerin to form microgels.
  • Dispersions are acidic with a pH ~3. Upon neutralization (pH 7), particles swell to around 1000 times their initial volume and the viscosity dramatically increases due to charge repulsion.
  • Can produce clear gels in water and ethanol due to refractive index matching.
  • Highly crosslinked carbomers are commonly used as super absorbers in disposable diapers.
  • Salts can decrease viscosity by reducing the charge repulsion.

Applications

  • Carbomers are listed in the USP-NF, PhEur, BP; JP, IP and ChP.
  • Grades with residual benzene content > 2 ppm do not meet the specifications of current pharmacopoeia monographs.
  • Carbomers with low residuals of other solvents other than the ICH-defined Class 1 – 2 solvents may he used in Europe.
  • Carbomers with low residuals of ethyl acetate, such as Carbopol 971P NF, are permitted for use in oral preparations, e.g suspensions, capsules or tablets.
  • For topical products, carbomers can be used as gelling agents (0.1 – 2.0%), controlled-release agents (5 – 30.0%), emulsifying agents (0.5 – 1.0%), emulsion stabilizers (1.0%), rheology modifiers (0.5 – 1.0%) and stabilizing and suspending gents (0.5 – 1.0%).
  • Carbomers are also employed as emulsifying agents in the preparation of oil-in-water emulsions for external administration.
  • Carbomers can be used as bioadhesive polymers (0.1 – 0.5%), tablet binders (0.75 – 3.0%) and controlled release agents.
  • Carbomers can aTopical medical devices (Ultrasound adhesive gel and personal and medical lubricants, and artificial tears)

Advantages

  • Versatile and multifunctional excipients for oral (solid and liquids) and topical formulations.
  • Synthetically derived, hence free from irregularities of natural products.
  • Available in multiple grades and properties to meet different formulation or product performance requirements.
  • Highly efficient thickeners at very low levels (<1% polymer). Suspensions and emulsions are efficiently stabilised due to the high yield value gels.
  • Can make aqueous or alcoholic clear gels.
  • Can make emulsifier free oil in water crème gel formulations.
  • Can make stable water in oil in water emulsions.
  • Excellent skin feel (<.5%) and shear thinning rheology.

Formulating Tips

Picture credits: Silverson FLASHBLEND Mixer

  • Lightly cross-linked carbomers (lower viscosity) are more efficient at controlling drug release compared with highly cross-linked carbomers (higher viscosity).
  • If used in wet granulation processes, water, solvents or their mixtures can be used as the granulating fluid. To control tackiness of the wet mass include talc in the formulation.
  • Carbomers from different manufacturers or grades produced via different manufacturing processes may not have identical properties. Therefore, grades should not be interchanged without performance equivalency ascertainment.
  • When preparing carbomer gels, powders should first be dispersed into vigorously stirred water, taking care to avoid the formation of agglomerates.
  • The dispersion should then neutralized by the addition of a suitable base.
  • Use granulated grades to reduce dusting issues during manufacturing.
  • Carbomers can easily be added to emulsions by addition to the oil phase prior to emulsification.
  • Adding electrolyte or small amounts of acid to the water phase prior to Carbomer addition significantly improves its dispersion by reducing solution viscosity. Up to 5% dispersions of Carbomer in water can typically be made with this approach.
  • Agitation of the dispersion should be done carefully and gently with a broad, paddle-like stirrer to avoid introducing air bubbles.
  • The viscosity of gels is significantly reduced at pH values less than 3 or greater 9, or in the presence of strong electrolytes.
  • Suitable neutralising agents include amino acids, potassium hydroxide, sodium bicarbonate, sodium hydroxide, and organic amines such as triethanolamine.
  • One gram of carbomer is neutralized by approximately 0.4 g of sodium hydroxide.
  • A number of manufacturers have introduced grades to overcome the challenges of dispersing powders in aqueous solvents, e.g Lubrizol’s Carbopol Ultrez.
  • Gels rapidly lose viscosity on exposure to UV light. To minimise this add a suitable antioxidant.

Leading Manufacturers of Carbomer Excipients

Recommended Carbomers for Pharmaceutical Formulations

  • Ultrez 30 (Lubrizol) has been shown to exhibit better electrolyte tolerance than other grades of Carbomer.
  • Ultrez 10 (Lubrizol) is a universal carbomer for broad applications. A 5% dispersion of Ultrez 10 exhibits viscosities in the 50 – 55 MPa s range.

Gellan Gum

What is it?

Gellan gum is a water soluble anionic hydrocolloid produced by the microorganism Sphingomonas elodea. This microorganism was discovered in 1978 in the United States by scientists at Merck following a concerted effort to find naturally occurring hydrocolloids.

Gellan gum is supplied as a free-flowing white powder. For commercial grades, gellan gum is manufactured by fermentation of a carbohydrate. In its native state, Gellan gum has acyl groups in its structure. Treatment with alkali removes acyl groups completely

 

Chemical and physical properties

Chemical Structure

Gellan gum is a straight chain polymer consisting of D-glucose, L-rhamnose and D-glucuronic acid units. In its native or high acyl grade, acetate and glycerate substituents are present on one of the glucose residues. The low acyl grade there is no acyl substituents. Note that the presence of acyl groups has a strong bearing on gel properties of Gellan gum.

 

A comparison of some of the main physical properties of High Acyl and Low Acyl Gellan Gum

High Acyl Gellan Gum (KELCOGEL® LT100 Low Acyl Gellan Gum
Molecular weight 1 – 2 x106 Daltons 2 – 3 x105 Daltons
Solubility Hot water Cold or hot water
Set Temperature (oC) 70 – 80 30 – 50
Thermoreversibility Thermoreversible Heat stable

 

Where can you use Gellan gum?

Gellan gum is a useful and effective gelling agent in pharmaceutical and food products. It offers the following benefits:

  • It is effective at low concentrations
  • Provides a wide range of viscosities and textures
  • Gels on cooling
  • Forms fluid gels, which are solutions with a weak gel structure. These systems are extremely versatile for suspending drug substances without settling
  • Can be used in combination with other hydrocolloids

 

Typical applications of Gellan gum include:

Application Typical products
Oral suspensions (immediate and sustained release) Ibuprofen, Paracetamol, Cetirizine
In-situ forming gels Nasal and ophthalmic products
Medicated gummies Vitamins and children medicines
Hair care products Stabilization of medicated shampoo formulations
Topical products Creams and lotions as a substitute for paraffins
Tablet coatings To improve slip and enhance swallowing
Oral care In toothpaste formulations to bind actives while creating a gel-like texture

 

Regulatory status

Approved for use in foods in Europe, USA, Japan, China and India. Gellan gum is also approved for use in non-food, cosmetics and pharmaceutical formulations in the USA, Canada, Australia, Brazil and China. Pharmaceutical use in EU falls under E418 (Directive EC/95/2). Gellan gum is manufactured in accordance with applicable food GMPs and complies with purity criteria defined in the current USP-NF monograph.

 

References

KELCOGEL® Gellan gum book, 5th Edition, CP Kelco, San Diego, USA

Mahdi M H et al., 2014. Evaluation of Gellan gum fluid gels as modified reléase oral liquids. International Journal of Pharmaceutics, 475; 335 – 343.

Kubo W et al., 2003. Oral sustained delivery of paracetamol from in-situ gelling Gellan and sodium alginate formulations. International Journal of Pharmaceutics, 258 (1-2); 335 – 343; 55-64

 

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