Poor Bioavailability of Rifampicin- A Global Emergency

Satish Balkrishna Bhise* and Sevukarajan Mookkan

 

Department of Biopharmaceutics, Government College of pharmacy, Karad-415124(M.S).  India.

* Corresponding Author E-mail: msevukan@rediffmail.com

 

ABSTRACT

The use of Fixed dose combinations (FDCs) of antitubercular drugs in the short course chemotherapy of tuberculosis is

being promoted internationally. However poor bioavailability of rifampicin has been perceived as a major bottleneck in successful treatment of tuberculosis. It perhaps is amongst one of the contributory factor which may lead to increasing resistance to anti-tubercular drugs. The present article critically focuses on various probable physical and/or chemical reasons responsible for poor/variable bioavailability of rifampicin in FDC and suggests the various approaches which may be successfully employed to overcome the aforementioned problems associated with rifampicin in FDCs.

 

KEY WORDS  Rifampicin, FDC, Bioavailability.

 

INTRODUCTION:

Tuberculosis   remains   one   of   the   most   common infectious diseases in the world.   Nearly one third of the global population is infected with Mycobacterium Tuberculosis; more than eight million people develop active tuberculosis every year and about two million people die.1  Out of total number of cases reported, 27 %  of  sputum  positive  infection  cases  are accommodated in South East Asia alone.2 In India, the number of deaths due to tuberculosis is estimated to be approximately 5,00,000 every year.3  Apart from that co-infection with the human immunodeficiency virus is a further increasing danger that could prove even more serious.  The disease has been righteously declared as a global emergency.

 

Controlling the spread of this global epidemic by BCG vaccination and chemoprophylaxis seems to be unsatisfactory. Treatment with anti-tuberculosis drugs becomes the only available option.  But in recent years, treatment of tuberculosis has been threatened by increasing number of patients with drug resistant tuberculosis.4  The  world health organization (WHO) suggested that treatment of drug resistant tuberculosis requires multi-drug therapy.    Multi drug therapy comprises of initial intensive phase with three to four first line anti-tubercular drugs for two months and continuation phase with two drugs for next four months.5 Due to this complex procedure, patients have to consume a large number of tablets causing patient non-compliance and treatment failure.

 

 

Need of FDCs combinations and its problem

Emergence of drug resistance presents a major threat to the future success of  tuberculosis control. Drug resistance in most tuberculosis patients predominantly arises as a result of multiple interruptions of treatment. When using single drug formulations, patients are more prone to interrupt their treatment on some drugs. The failure of antitubercular therapy is essentially due to non-compliance or partial compliance with the recommended therapy.

 

To overcome treatment failure and increase the patient compliance, the World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUALTD) recommends the use of the four drug fixed dose combination (4FDC) tablet containing rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol hydrochloride 275 mg, as well as 3 FDC and 2 FDC combination tablets.5  Fixed dose combination is a combination of two or more first line anti-tubercular drugs in a single formulation at a fixed proportion.  Thus FDC is a simple approach to deliver the correct number of drugs at the right dose as all the necessary drugs are combined in a single tablet.  Other inherent advantages of fixed dose combination are patient adherence, reduced risk of emergence of drug resistant strains, lower cost of treatment, less risk of medication errors, simplified drug supply management, shipping, distribution, simplification and effective implementation of Directly observed Treatment short course (DOTS). 6, 7

 

However  the  major  quality  issue  with  FDC  tablets  is assuring the bioavailability of rifampicin. It is known that when rifampicin is combined with other antitubercular drugs in the  same formulations, its bioavailability is  negatively affected if formulations / processes are not optimized and quality  of  active  drugs  is  not  controlled.  Bioavailability problems of  rifampicin may  result  from  changes  in crystalline form of rifampicin during the tabletting process.8  Besides being poorly soluble in  water, the absorption of rifampicin is adversely affected by food. Rifampicin  alone,  in  solid  state,  is  stable  but  its stability   in   the   presence   of   moisture   and   other tubercular drugs together is questionable. Rifampicin is incompatible in the presence of water. Ethambutol hydrochloride, which is a highly hygroscopic material, tends to catalyze rifampicin and isoniazid interaction. World health organization (WHO) and the international union against tuberculosis and lung disease (IUATLD) in their joint statement in 1994 advised that only FDCs of   good   quality   and   proven   bioavailability   of rifampicin should be used.9       A protocol has been published for testing of bioequivalence of rifampicin form FDC products.10

 

 

This review article will discuss the probable reason for the variation in bioavailability of rifampicin form the FDC formulations and the possibility to encounter this problem.

 

Fig 1. Rifampicin degradation mechanisms/pathway.

 

Polymorphism

Polymorphism is one of the important factors influencing the bioavailability of rifampicin and the effectiveness of treatment.   Apart from that the changes from one form to another  form  during  processing  and  tabletting  are  the reasons for the variable bioavailability of rifampicin from fixed dose products.

 

Different polymorphic forms are dependent upon molecular interaction, hydrogen bridges, change in conformation and ionization states, they cause molecular reorganization, forming unitary cells and their repetition, causes a crystalline reticule   that   characterizes   the   crystal.   The   crystalline structure adopted by active substance causes changes in the properties  of  solid-state  formulations.  These  can  affect properties such as solubility, fusion points, density, dissolution velocity, refraction index, reaction speed, stability,  hygroscopicity,  crystal  hardness,  enthalpy  and phase diagrams. When rifampicin polymorph I and II as well as amorphous form which was prepared by freeze drying method were characterized by thermal and spectroscopic methods.  It revealed the thermal events that took place in the   rifampicin   samples.   Form   I   demonstrated   sharp exothermic  decomposition  at  255  –266°c,while  form  II shows melting endotherm at 180-197°c followed by recrystallization to form I at 197-223°c, which is a characteristic of solid-liquid - solid transmission and finally decomposes at 247 –266°c The amorphous form presents exothermic  event  starting  from196°c  with  decomposition taking  place  at  around  258°c.  From  this,  finding  the existence of a dynamic thermal relationship between two polymorphs of rifampicin has been established. The formation of crystalline form I after heating form II is an irreversible process thereby inferred that form I is stable, while form II is meta stable. Thermogram of the amorphous form shows good thermodynamic stability with decomposition at 258οc.14

 

BIOPHARMACEUTICAL ASPECTS:

Particle size

Particle sizes have a significant impact on drug absorption for a drug falling in class II of BCS11. As rifampicin is a borderline class II drug12, (table no1) effect   of   particle   size   is   more   pronounced   in determining         rate and extent of solubility. Bioavailability  of  the  drug  depends  on  absorption number (An), dissolution number and  dose  number. For BCS class II drugs absorption is high and hence bioavailability is a function of dissolution number, which is proportional to initial radius of drug particle size.13

 

 

Fig 2. Mechanism of enhancement of decomposition of rifampicin in the presence of  Isoniazid.

 

The   particle   sizes   below   100   µm   have   higher dissolution rates irrespective of the physical nature of the rifampicin powder, while particle size with more than 100 µm have slower dissolution rate. At the same time  bioavailability  of  rifampicin  is  reduced  when particle size is in the range of 10µm due to the presence of electrostatic changes causing  aggregate  formation.14  Thus the optimum particle size range of 10 -100 µm will be a desired one for the formulation. Thus it seems that the effect of polymorphism or physical nature of rifampicin on dissolution is negligible while bioavailability is mainly governed by particle size.

 

 

Differences in the hydrogen bonding of form I, II and amorphous form can be revealed by FTIR spectroscopy15. In rifampicin all the functional groups which can be involved in hydrogen bonding are bonded intramolecularly. It shows differences in ansa OH, furanonic, acetyl and amide C=O frequencies. Form II shows characteristic double peaks at 1712 and 1734-1 due to acetyl and furanone C=O groups. Wherein forms I and amorphous show only a single peak at1725 cm-1 and also ansa OH gives sharp bond at 3481cm-1  for form I while form II and amorphous it is a broad bond over 3565-3150cm-1.Thus based on the differences between furanone and acetyl and ansa OH infrared spectrum can serve as a qualitative tool for the determination of physical form of rifampicin.14 P-XRD studies reveals the characteristic diffraction patterns of both polymorphs.  Form II shows sharp signals while form II with amorphous nature the intensity of signals are dropped but in case of amorphous form no patterns were observed.16 NMR spectrum analysis is important in estimation of structure, conformation and crystallographic characterization of polymorphs   as it can determine the nature of polymorphism at molecular level.

 

Fig 3.   Schiff’s reaction of rifampicin and isoniazid

 

As   rifampicin   is   a   borderline   class   II   drug   of Biopharmaceutics Classification System (BCS), where rate and extent of dissolution are critical for optimum bioavailability. Efforts should be taken to determine and   limit  the   physical  forms  in   the   commercial samples. The solubility and dissolution properties of five different rifampicin raw materials were reported of which three were polymorphic II and two were mixture forms II and an amorphous form. The dissolution behavior of five samples was seen in 0.1N HCL, Phosphate buffer pH 7.4 and water. From these studies it was revealed that the difference in the dissolution behaviors in water and in the phosphate buffer but no difference in 0.1N HCl 16. Molecular modeling studies showed that form II exhibits higher solubility; hence it is suitable form for the formulations, and also reported that amorphous form showed reduced dissolution rate due to high electrostatic interactions in amorphous portion.

 

Stability aspects

In fixed dose combination of antitubercular formulations, rifampicin is one of the most critical component with respect to stability and bioavailability. Therefore, it should be protected from exposure to air, humidity, light and excessive heat. The possible mechanism of rifampicin degradation pathways are shown in the figure (1). Under alkaline condition, rifampicin is prone to auto oxidation, at the para phenolic  group  in  the  naphthalene  rings  in  presence  of oxygen at room temperature, to give Rifampicin-quinon17. This oxidation can be prevented by use of antioxidants like sodium ascorbate.  Rifampicin is also prone to acid catalysis in the stomach and consequently undergoes a  process of hydrolysis to give degradation products of 3- formyl rifampicin and 1-amino –4-methyl piperazine. (Fig 2) Apart from   this,   degradation   of   rifampicin   under   different pH/medium, temperature are given in Table 2.

 

Drug degradation in the formulation

In recent years number of articles has been published are dealing with the reduced    bioavailability of rifampicin used in  combination  with  isoniazid,  pyrazinamide,  and ethambutol. These drugs are considered as first line treatments of tuberculosis. The stability of suspension containing rifampicin, isoniazid and pyrazinamide at various temperatures  was  studied.  It  indicated  that  the decomposition of rifampicin is insignificant when present alone or in combination with pyrazinamide but the degradation is as high as 98% in the presence of isoniazid.18

 

When the stability of rifampicin in the acidic medium in the presence of isoniazid. Rifampicin hydrolyzes in acidic medium to  form insoluble and  poorly absorbed 3-formyl

rifampicin SV (3-FRSV). The degradation rate of rifampicin in the acidic medium alone and in the presence of isoniazid was calculated. The degradation kinetics of rifampicin follows first order reaction and the rate constant (K) was found to be 2.1 × 10-3 min-1.   The degradation rate is accelerated in presence of isoniazid to give (k) 4.6 ×10-3 min-1. From this study the author indicated that degradation of rifampicin in separate formulations was 12.4 % but in case of FDC the degradation was 21.5%. This may address the probable reason for poor/ variant bioavailability of rifampicin in fixed dose combination. 19

 

Fig 4. Carbonyl condensation of rifampicin and isoniazid

 

The reason for poor bioavailability of rifampicin in the presence of isoniazid leads to formation of hydrazones, via 3-formylrifamycin under acidic conditions. It interacts  with  isoniazid through a  fast  second  order reaction.    Due  to  instability of  hydrazone in  acidic conditions, it regenerates into isoniazid and 3- formylrifamycin by pseudo first order reaction. As the second order forward reaction is faster than the first order backward reaction, the overall reaction is favoured, towards formation of hydrazone. As a result, the decomposition of rifampicin to 3-formylrifamycin is pushed forward and an overall enhancement of degradation of rifampicin is observed resulting into its poor bioavailability 20 21(fig 2). Also 3-formylrifamycin could possibly undergo sciff’s reaction to form a complex with isoniazid. The carbonyl groups of 3- formylrifamycin and amino groups isoniazid may rearrange to  form an  iminium ion.  The  4-  hydroxy group enhances the complex formation by forming hydrogen bond  with  hydrogen atom attached  to  the nitrogen   atom.   In   addition,   carboxylic   acid   and alcohols can also undergo carbonyl condensation reactions. Isoniazid reacts with rifampicin in this manner, which could account for the instability of the rifampicin when present together with isoniazid. This interaction also occurs between rifampicin and pyrazinamide;   however,   it   has   been   frequently observed that isoniazid caused further rifampicin instability compared to pyrazinamide. The reason for this could be due to the fact that the carboxylic acid and alcohol further undergo Fischer’s esterfication reaction. The hydroxyl groups of rifampicin are readily able to react with the aqueous carboxylic acid degradants yielded by isoniazid and pyrazinamide to form an ester22 (fig. 3, 4, 5).

 

Fig 5. Fischer’s Esterfication between rifampicin /isoniazid.

 

Table 1. BCS classification of antitubercular drugs

 

Drugs	BCS class
Rifampicin	2 (tentative)
Isoniazid	1 (tentative)
Pyrazinamide	1
Ethambutol 2HCl	3 (tentative)

 

Modification of rifampicin formulation

It has been reported that degradation of rifampicin is influenced only by the presence of isoniazid under acidic conditions and not by Pyrazinamide (PZA) or Ethambutol (EMB).   The   mechanism   was   suggested   to    involve interaction of 3-formyl rifampicin and isoniazid leading to the formation of isonicotinyl hydrazone of 3- formylrifampicin (HYD). The permeability study shows that rifampicin is mainly absorbed in the stomach and duodenum while Isoniazid shows higher permeability in the intestine. The permeability of rifampicin is significantly influenced by the Isoniazid in the stomach and jejunum but reverse is not the case.24  The problem of reduced bioavailability of rifampicin can be avoided by segregating the release of both drugs in the different regions where it shows good permeability. To achieve this, new FDC formulation should be developed to first release the rifampicin in the stomach and then the isoniazid should be delivered later in the intestinal region.

 

Packaging requirements for the FDC formulation

Rifampicin alone, in solid state, is stable but its stability in the  presence  of  moisture  and  other  anti-tubercular drugs together  is  questionable. Hence  the  development of  four drug FDCs containing rifampicin demands not only improving the solubility of rifampicin but also protecting it against oxidation and interaction with the other drugs. Rifampicin is  incompatible with isoniazid in  presence of under  accelerated  conditions  in  presence  and  absence  of light is far less than the three- or four- drug combinations containing PZA and/ or  EMB along with rifampicin and Isoniazid combination demonstrating the  catalytic role  of PZA and EMB in the reaction Ethambutol hydrochloride, which  is  highly  hygroscopic  material,  tends  to  catalyse rifampicin and isoniazid interaction.   The catalytic role of PZA in the degradation reaction is still not clear and the mechanism should be studied further for better understating. The four FDC tablets should be protected from exposure to moisture   and   light.   In   this   regard,   the   current   USP monograph includes a limit for loss on drying of 3%m/m for the FDC tablets.  The need of a tighter barrier packaging for the 4 FDCs tablet should be considered seriously and the proven stability products should only be approved by the regulatory agencies for the marketing.

 

A comparative bioavailability study of rifampicin after administration of single component rifampicin capsule and   rifampicin-isoniazid   fixed   dose   combination capsule formulations demonstrated a significant decrease in  pharmacokinetic parameters. Cumulative amount of rifampicin and the major metabolite compound 25-DAR excreted in 24 h was reduced to the extent of about 32.35 and 27.90 % respectively in the rifampicin –isoniazid FDC capsule formulation. Peak excretion rate for rifampicin and 25-AR showed a reduction of 21.18 and 24.03 % respectively, and the AUC 0-24 values showed a corresponding decrease to the extent of 34.24 and 29.26 %. Thus these studies concluded that bioavailability of rifampicin is significantly impaired in presence of isoniazid in fixed dose combinations compared to formulation containing rifampicin alone. 23

 

Table 2.  Rifampicin degradation in various pH/ Temperature

Drug	pH       / medium	Temperature	Degradation product
Rifampicin	0.1N HCL	37 0c	3-formyl rifampicin
	2-3	20-22 0c	3-formyl rifampicin
	8.2	0 20-22  c	Rifampicin quinone
	8.2	0 60-70  c	25-desacetyl rifampicin 25-desacetyl- 21acetyl rifampicin 25-desacetyl- 23cetyl rifampicin
	NaOH 5% in ethanol- water (1:1)	20-22 0c	25-desacetyl rifampicin

 

Compatibility issues with excipients

The  pharmaceutical excipients like  bentonite,  kaolin and talc have strong adsorption of rifampicin, which cause reduced gastrointestinal absorption of rifampicin, 26,27  and also bioavailability of rifampicin is significantly affected when it is administrated along with  antacids  like  aluminum  hydroxide,  magnesium trisilicate, and sodium bicarbonate. This may be due to the combined effect of gastric pH elevation, formation of chelation between drugs and aluminum ion and binding of rifampicin with magnesium trisilicate.28

 

 

Besides the excipients discussed above an important finding regarding sodium laruyl sulphate as an exipient was revealed during an investigation in our laboratory. We identified that when sodium laruyl sulphate was used along with rifampicin, it significantly reduced the solubility of the rifampicin in in- vitro dissolution medium. The underlying cause for the negative impact on solubility of rifampicin may be correlated to the fact that there is complex formation between rifampicin and sodium  laruyl  sulphate  which  leads  to  its  reduced  solubility. Thus it can be inferred that the excipients used in formulation of rifampicin have a direct impact on solubility and poor bioavailability of the drug from the fixed dose combination of antitubercular therapy. So,   the   selection   of   suitable   excipients   for   the rifampicin formulation should be carefully evaluated by means of pre-formulation studies.

 

CONCLUSION:

FDC tablets with poor rifampicin bioavailability could directly  lead  to  poor  treatment  outcome  and  may create, not prevent, drug resistance. Good quality FDC tablets with demonstrated bioavailability of rifampicin are an absolute requirement for successful treatment outcomes  in  programmes  utilizing  FDC-based regimens.     The     various     physicochemical     and biopharmaceutical factors that may lead to poor bioavailability of rifampicin from fixed dose combination of anti-tubercular drugs are different polymorphic forms, dissolution as a function of particle size, stability of rifampicin in the FDC formulation, decomposition reactions in different pH /media, temperature variation, rapid decomposition of rifampicin in presence of isoniazid in situ in stomach acidic conditions and interaction with pharmaceutical excipients. This problem may be addressed by reformulation of FDCs that have improved bioavailability and stability of rifampicin. For example the problems can be solved by following different approaches, like 1) controlling the particle size of rifampicin between 10 to 100 µm for better dissolution and thus increase the bioavailability and preventing the change of polymorphic forms II to form I during the manufacturing process and throughout the shelf life of the formulation, 2) The applications of Good Manufacturing practices to guarantee that the formulation has good quality and consistent quality is achieved every time. 3) Modification of pH in the stomach, to decrease the decomposition of rifampicin in the acid medium by soluble alkali such as sodium bicarbonate, administered concomitantly with FDCs. The choice of alkalizing agent should be selected carefully, due to formation of chelation with rifampicin that can modify its bioavailability 4) Modification of delivery patterns of rifampicin and isoniazid in such a way that isoniazid is delivered in the upper part of intestine and rifampicin in the stomach region or by enteric coating of isoniazid to avoid the contact with rifampicin in the stomach and thus rifampicin degradation. 5) Selection of suitable tight barrier packaging materials to  protect form moisture and light and thus preventing the degradation of rifampicin and isoniazid in the FDC formulation. Consequently, development of a simple in-vitro dissolution test will surrogate for quality evaluation of rifampicin containing  FDCs  instead  of  conducting  human bioavailability studies. In this regards US Pharmacopoeial monograph specifies pH 6.8 phosphate buffer as dissolution medium for 4FDC tablets and HPLC for analysis of all four of the drug substances in the dissolution samples.

 

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Accepted on 28.08.2008   © RJPT All right reserved