Alteração dissolução de cápsulas

Alteração dissolução de cápsulas

(Parte 1 de 5)

36 Pharmaceutical Technology APRIL 2002 w .phar mtec anufacturers ofpharmaceutical products have the responsibility — not only from marketing and ethical standpoints but also from a legal (regulatory) perspective — to ensure that their products meet dissolution specifications during storage conditions described on the label.This is necessary because dissolution per se is rate determining in terms ofthe absorption and bioavailability of a drug.

Unfortunately,a few dosage forms exist in which eventual change in the dissolution characteristics is a common problem. Formulations containing gelatin in the outer layer (i.e.,hard and soft gelatin capsules) as well as sugar-coated tablets are typical examples.The problem has been ascribed to cross-linking of gelatin,which occurs with time.Because ofthis tendency,the very use ofgelatin in pharmaceutical formulations has been put to question.Nevertheless,the material is used widely despite efforts to replace it with other substances.

This article reviews the literature describing the widespread problem ofa drop in dissolution rates ofgelatin-containing products and critical observations concerning their in vitro and in vivo behavior.The discussion includes a briefintroduction to gelatin,some reported instances ofaltered dissolution profiles,the chemistry ofchange,responsible factors,suggested test methods,and reported solutions to the problem.

Gelatin — a brief introduction Gelatin is a mixture ofwater-soluble proteins derived from collagen by hydrolysis (1).The protein fractions consist almost entirely ofamino acids (see Table I).These amino acids are joined by amide linkage to form a linear polymer varying from 15,0 to 250,0 Mw. Types of gelatins.The two types ofgelatins are characterized by their mode ofmanufacture.Type A gelatin (pH 3.8–6.0;isoelectric point 6–8) is derived by acidic hydrolysis ofpork skin and contributes plasticity and elasticity to the blend.Type B gelatin (pH 5.0–7.4;isoelectric point 4.7–5.3) is derived by basic hydrolysis ofbones and animal skin and contributes high gel strength to the blend.Gelatin used in the pharmaceutical industries is a blend ofthese two types (2),although sometimes

Alteration in

Dissolution Characteristics of

Gelatin-Containing Formulations

A Review of the Problem,Test Methods,and Solutions Saranjit Singh,* K.V.Rama Rao,K.Venugopal,and R.Manikandan

Saranjit Singhis a professor and department head, andK.V. Rama Raois a postgraduate student, at the Department of Pharmaceutical Analysis of the National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, India, tel. 91 172 214 682, fax 91 172 214 682, K. Venugopal and R. Manikandan are postgraduate students from the same institute, presently working at Ranbaxy Research Laboratories (Gurgaon, India).

*To whom all correspondence should be addressed.

MThe authors review the literature about the problem of the alteration in dissolution characteristics of gelatinbased formulations.This article also includes a brief introduction to gelatin as a pharmaceutical ingredient and describes examples of the altered dissolution profile;the established cause, mechanisms,influencing factors,and stress methodsfor study of the behavior; methods for determining the nature and extent of the change;and the reported solutions to the problem.

38 Pharmaceutical Technology APRIL 2002 w .phar mtec only Type A or Type B is used.Various grades of gelatin with differing particle sizes and molecular weight are sold commercially in the form oftranslucent sheets,granules,or powders.Gelatin usually is graded according to jelly strength,expressed as bloom strength,which is the weight in grams that, when applied with a 12.7 m–diameter plunger, will produce a depression exactly 4 m deep in a matured jelly containing 6.6% w/w ofgelatin in water.

Properties.Gelatin is practically odorless and tasteless.It is insoluble in acetone,chloroform, ethanol (95%),ether,and methanol.It is soluble in glycerin,acids,and alkalis,although strong acids or alkalis cause its precipitation.It swells and softens in water,gradually absorbing 5 to 10 times its own weight in water.It solubilizes in hot water. Upon cooling to 35–40 °C,it forms a jelly or gel. At temperatures 40 °C,the system exists as a sol. A gel ofhigher viscosity is formed in alkaline media as compared with acid media (3).

Because it is a protein,gelatin exhibits chemical properties characteristic ofthose materials (e.g.,gelatin is hydrolyzed by most ofthe proteolytic systems to yield its amino components).Gelatin reacts with acids and bases,aldehydes and aldehydic sugars,anionic and cationic polymers,electrolytes, metal ions, plasticizers, preservatives, and surfactants.

Applications and uses.Gelatin is valuable to the pharmaceutical industry because it can be incorporated into a variety of formulations.It is the only ingredient used to form hard and soft elastic gelatin capsules (SEGCs).It is widely used in solutions, syrups, tablets, sugar-coated tablets, inhalants, and dental,vaginal,and topical preparations and injections.Its other uses include the preparation ofpastes,pastilles,pessaries,and suppositories.In addition,it is used as a vehicle for parenteral formulations and as a tablet binder and coating agent.Low molecular weight gelatin has been investigated for its ability to enhance dissolution oforally ingested drugs.

Gelatin also is used for the microencapsulation ofdrugs,a process whereby the active drug is sealed inside a microsized capsule that then may be handled as a powder.Gelatin forms simple coacervates at temperatures 40 °C in the presence of dehydrating agents such as ethanol or 7% sodium sulfate solution.Peters et al.studied the properties ofgelatin in complex coacervation processes (4).Gelatin capsules also can be coated for any application (5).Soft gelatin capsules can be given a film coat (6) and an enteric coat (7).

Cross-linking ofgelatin before or after drying the capsules allows for sustained release ofthe drug (8).Formaldehyde exposure has been exploited to produce enteric hard and soft capsules (2,9,10).Drilling pores in formaldehyde cross-linked gelatin capsules to design a controlled-release dosage form also has been reported (1).A zero-order release ofverapamil was observed with this approach.Several other reports describe the formation ofgelatin microspheres and their cross-linking with glutaraldehyde with the objective ofsustaining drug release (12–14).Cross-linked gelatin gels have been used as biomate- rials in living tissues either as bioadhesives or as devices for sustained drug release (15).A novel system for gene delivery based on the use ofDNA-gelatin nanoparticles (nanospheres) formed by salt-induced complex coacervation ofgelatin and plasmid DNA has been developed.It consists ofspherical particles in sizes ranging from 200 to 700 nm containing 25–30% (w/w) DNA.The particles are stabilized by the cross-linking ofgelatin (16).

Therapeutically,gelatin has been used as a plasma substitute and in the preparation ofwound dressings.Soft capsules made ofgelatin and containing a radiolabeled drug have been used in radioactive tracer studies (17).Gelatin also is widely used in food products and photographic emulsions.

In general,when it is used in an oral formulation,gelatin may be regarded as a nontoxic and nonirritant material.However,rare reports exist ofgelatin capsules adhering to the esophageal lining (18–20),which may cause local irritation. Hypersensitivity reactions,including serious anaphylactoid reactions,have been reported following the use ofgelatin in parenteral products (21).

Official status.Gelatin is included on the FDA list ofinactive ingredients.In the United Kingdom,it appears on the list oflicensed medicines.It also is described in most pharmacopeias.

The problem of gelatin cross-linking and change in dissolution profiles A major problem with gelatin-based formulations is an apparent fall in dissolution upon aging,which is attributed to the cross-linking ofstressed gelatin-containing products.The crosslinking causes the formation ofa swollen,very thin,tough,rubbery,water-insoluble membrane,also known as a pellicle.The pellicle acts as a barrier and restricts the release ofthe drug.It is not disrupted easily by gentle agitation,and the dissolution values (Q values) drop often to the point ofrejection (2,2).

The altered dissolution behavior ofgelatin is reported in several studies in the literature.This section discusses examples for various categories offormulations.

Sugar-coated tablets (SCTs).In SCTs,gelatin forms part ofthe subcoat,where it is used mainly as a binder,film-forming agent, and coating agent.During the subcoating process,a coating solution and a dusting powder are applied alternately on the core, interspersed with relevant drying periods.This procedure results in the buildup ofa laminated structure or a thick sandwich ofalternate layers ofbinder and powder.These layers give the tablet a smooth profile by covering the core’s original sharp edges and facilitate the application ofthe final color coating, which seals the tablet.

The problem ofa reduced dissolution rate in SCTs was highlighted very early in a study by Khalil et al.(23).They developed a model subcoating system ofSCT formulations consist-

Table I: Amino acids and their content in gelatin.

Amino Acid Percentage Glycine 25.5 Proline 18.0 Hydroxyproline 14.1 Glutamic acid11.4 Alanine 8.5 Arginine 8.5 Aspartic acid6.6 Lysine 4.1 Leucine 3.2 Valine 2.5 Phenylalanine 2.2 Threonine 1.9 Isoleucine 1.4 Methionine 1.0 Histidine 0.8 Tyrosine 0.5 Serine 0.4 Cystine 0.1 Cysteine 0.1

40 Pharmaceutical Technology APRIL 2002 w .phar mtec ing mainly ofcast gelatin films containing sucrose,dextrose, fructose,and calcium carbonate.The films were stored at 70, 80,90,and 110 °C for varying time intervals,and a significant correlation was observed between an increase in the storage temperature and the rate at which these films dissolved.The disintegration and dissolution properties were adversely affected by an increase in temperature.

Subsequently,Barrett and Fell reported the influence ofage on the dissolution ofSCTs containing phenylbutazone (24). The formulations were stored at 20,37,and 50 °C.The resulting progressive decrease in disintegration and also ofdissolution was related to the adherence ofthe gelatin subcoat to the tablet core.The breakup pattern ofolder tablets (5 years old) was similar to that ofthe tablets stored at 50 °C.The disintegration time ofthe SCTs stored at 20 and 37 °C was not affected, except for that ofthe tablets stored for 14 weeks at 37 °C.

The retardation ofdissolution in sugar-coated cyclothiazide and reserpine tablets when stored for 1 year at various temperatures is reported by Warren and Rowe (25).Very poor dissolution rates also were observed in SCTs ofpropantheline bromide (26).El-Fattah and Khalil examined the dissolution rates of14 batches ofsugar-coated chlorpromazine hydrochloride tablets and found that all the batches passed USP disintegration tests in 0.1N hydrochloric acid,yet none passed the dissolution limit ofnot less than 80% dissolved in 30 min (27).Ondari et al.observed retardation in the dissolution ofthe marketed products ofsugar-coated chlorpromazine tablets stored at isothermal temperature (30 C) and cyclic storage conditions (12 h at 30 C,12 h at room temperature,12 h at 30 C and 90% RH) for 4 weeks (28).

In another study,the dissolution behavior ofeight commercially available brands ofibuprofen tablets was investigated after storage at 37 °C and 75% RH for 4 weeks (29).At the end of the storage period,a significant reduction in the dissolution rate ofSCTs was noted,but film-coated tablets were unaffected. The SCTs were associated with a loss ofclinical efficacy.In a study ofSCTs ofriboflavin,10 batches of2 brands were subjected to storage at temperatures ranging from 18 to 28 °C in a closed container and at 45 °C outside the container.The brand oftablets that contained gelatin in the subcoat exhibited poorer dissolution profiles than did the other brand (30).Dahl et al. found no change in the in vitro dissolution performance of gelatin-coated acetaminophen tablets that had been stored 7 months at room temperature (31).However,when the tablets were stored in the presence ofhigh humidity for 3.5 and 7 months,a significant reduction in both the amounts ofdrug released and standard deviation at each time point was observed.

Shah and Parsons compared the in vitro dissolution behavior offilm-coated,sugar-coated,and plain tablets ofvalproic acid (VPA) after subjecting them to accelerated storage conditions (32).The plain and film-coated tablets were not affected adversely by the accelerated conditions of40 °C and 75% RH for at least 3 months.The percent ofVPA released from SCTs after 1 month also was not significantly different.However,after 2- and 3-month storage periods,the percent ofVPA released during the first hour significantly decreased.The poor dissolution was ascribed to a disintegration problem in the sugar coating,but the fact that most ofthe core tablets still were dry at the end ofthe dissolution test indicated adherence ofthe seal coat or the subcoat to the tablet core.

In a recent study,Singh et al.studied the release rates ofSCTs ofchloroquine phosphate when exposed to various storage conditions such as 25 C and 60% RH,40 C and 75% RH,25 C and 60% RH/light,and 40 C and 75% RH/light (3).The storage ofSCTs at 25 C and 60% RH/light conditions for 16 days resulted in retardation ofthe dissolution rates.The storage of SCTs for 8 days in 40 C and 75% RH/light conditions caused a drastic retardation in dissolution.Storage in these conditions for more than 8 days resulted in an even worse performance.

Hard gelatin capsules (HGCs).The shell ofHGCs normally contains 13–16% water,and HGCs can be safely stored at between 40 and 60% RH.Variations within the range of12–18% moisture do not seriously impair the integrity ofthe shell.Ifan HGC shell contains 12% water,then it can become brittle and easily ruptured.Ifit contains 18% moisture,then the shell becomes moist,soft,and distorted and has a propensity to transmit moisture to the capsule contents ifthe contents are hygroscopic (34).The dissolution stability ofHGCs is determined primarily by the moisture content ofthe shell,which in turn is related to the storage conditions.The moisture in the capsule gelatin shells will act as a plasticizer to impart flexibility to HGCs. Variations in the moisture content ofa capsule shell as the storage conditions change may lead to undesired physical properties such as brittleness and stickiness.Moisture also can be transferred from the contents to the shell,potentially resulting in softening and stickiness problems.This problem is seen in efflorescent ingredients,for example.Conversely,moisture can move from the shell to the capsule contents during storage,especially for deliquescent and hygroscopic ingredients.Moisture transfer between shell and contents can be one ofthe reasons for a change in the properties ofgelatin when stored at 40 C, 50 C,and 40 C and 75% RH (35).

(Parte 1 de 5)