Quality of Quinine Preparations in Indian Hospitals and ... · To determine whether the quinine sulphate, quinine bihydrochloride, and cinchona febrifuge powders, available in the

QUALITY OF QUININE PREPARATIONS IN INDIAN HOSPITALS AND DISPEN-

SARIES

By INDU BHUSAN BOSE, ph.D. (Berlin) B. MUKERJI, m.b. (Cal.), m.d., d.sc. (Mich.)

and

R. N. CHOPRA, c.i.e., m.a., m.d., sc.d. (Cantab.), f.r.c.p. (Lond.)

BREVET-COLONEL, I. M.S.

(From, the Biochemical Standardization Laboratory, Government of India; All-India Institute of Hygiene

and Public Health, Calcutta)

Introduction

As early as 1907, Major-General Sir John

Megaw, late Director-General of the Indian Medical Service, called attention to the frequency with which patients seeking treatment for malarial fevers in various hospitals and dispen- saries failed to receive the doses of quinine which were prescribed for them. Later, Megaw, Ghosh and Chatterjee (1928) conducted an

enquiry on the quality and quinine content of nearly 100 stock solutions obtained at random from various hospitals and dispensaries in

Bengal and Assam. The results of this survey revealed that no less than 25 per cent of the

samples were 25 per cent or more weaker than the stated strength.

610 THE INDIAN MEDICAL GAZETTE [Oct., 1939

The Drugs Enquiry Committee appointed by the Government of India in 1930-31 (Chopra et al, 1931) collected a large number of quinine tablets from the various provinces of India

through the co-operation of the witnesses who

tendered evidence before the committee, and found on analysing them that a very large per- centage were either adulterated or contained

comparatively smaller proportions of quinine than that claimed by the manufacturers.

In the course of an all-India survey of the

quality of drugs and medicinal chemicals, the Biochemical Standardization Laboratory has, during the last two years, analysed more than 150 samples of quinine and cinchona prepara- tions. The results indicate, in no uncertain

terms, that the unsatisfactory state of affairs, which existed 30 years ago in this country with regard to the deficiency in the strength of

quinine mixtures and other preparations of similar category and which had been the subject of repeated warnings, still continues with un- abated intensity even to this day. If the condi- tion has changed at all, it has changed for the worse. In view of the gravity of the problem, it seems desirable that the medical profession should be aware of the real situation so that they can co-operate, if necessary, in any pro- gramme to eradicate the evil. The present paper is published with this idea in view.

Procedure

(a) Collection of samples.?Through the courtesy of the heads of medical and public health administrations of the various provinces of British India, a fairly representative collec- tion of quinine preparations of different cate- gories was made. These included stock quinine sulphate mixtures from the various hospitals and dispensaries, quinine sulphate tablets and

powders, quinine bihydrochloride tablets, powders and mixtures, and a host of other

quinine and cinchona preparations such as

ammoniated tincture of quinine, quinine ethyl carbonate, quinine tannate,

'

quinetum', cin- chona febrifuge, tincture of cinchona, compound tincture of cinchona, etc. The stock solutions of mixtures were received generally in sealed bottles with a label containing a statement

regarding the amount of quinine said to be

present per ounce of the mixture. The tablets and powders of the quinine salts and other solid preparations of cinchona were obtained generally in sealed paper packets and, sometimes, in

original unbroken glass or tin containers. A few brands of quinine tablets were bought by the officers of the laboratory from the open market, while a few others were presented to the laboratory for analysis by certain commer- cial firms and independent medical practitioners. The names of the manufacturers were obtained in as many cases as possible, but information regarding the dates of purchase, countries of origin, and conditions of storage of the samples were not available in some instances.

(b) Methods of analysis.?The analytic1, methods employed for the determination 0

purity of the preparations mentioned above a

^

chiefly those described in the British Pharffla^ copoeia, 1932. Cinchona febrifuge samples haV been assayed according to the details laid under 1

quinetum' in the British Pharmaceutic Codex (1934) and also under

'

totaquina ' in t

British Pharmacopoeia, 1932. t

To determine accurately the quinine conte^ of the stock mixtures of quinine, an aliquot p? tion (about 10 c.cm.) was first made alkalin_ with ammonia or caustic soda solution and the

extracted with chloroform until complete extr^c tion of the alkaloids took place. The chl?r form containing the alkaloid in solution ^^ then removed, treated with about 1 to 2 c.cm- ^ 95 per cent alcohol, and evaporated to dryne^ at 110?C. till constant weight was

The residue, which represents the quinine ba^' was weighed and the weight of the corresp01? ing salt calculated from this figure. The c

^ chona febrifuge mixtures are treated in a

^.jlC the same manner as the quinine mixtures, ,

content of total alkaloids being determine '

instead of quinine alone, in such cases. In a large majority of cases, dupllC.^s

analyses have been carried out by two chem1^ working independently. There are a number instances, however, where this was not possl

'

owing to insufficient quantities of the specif being supplied for analysis by the Pal concerned.

Results nCI ? \00

A summary of the results of analyses oi ^

so-called '

quinine mixtures' is presented ̂ table I. The majority of these samples y of 100) are stock mixtures of quinine sU P~L]y this being the salt of quinine most c0.133111^- employed for routine treatment in Indian ?

pitals and dispensaries. A few cinchona le -eg,

fuge mixtures are also included in the se,oC}c Out of a total of 100 samples, only 20 ?

^ mixtures (20.0 per cent) are up to standar are found to agree with the claims made by

senders, on the labels attached to the_ bo ^ Sixty-four samples have shown a deficiently quinine, of which as many as 23 samples (n<j ef

one-third) are found to contain less than ^ eJ) cent of the stated strength of quinine. eI3t samples contain from nil to about 30 VeV -njy of the quinine salt claimed. This is cer a^,jy a very disquieting state of affairs, parties when it is observed that the majority 0

^eep, samples reported upon in this paper have r

received from government or governmen pies trolled hospitals and dispensaries. If sfl apd could be secured at random from private charitable dispensaries, there is little doub ^ ̂

a worse state of affairs would be found to , 0f Slight variations in the quinine conte ^

hospital mixtures may well be ignored anCcy of presumably be accounted for by inaccura

?CT-, 1939] QUALITY OF QUININE PREPARATIONS : BOSE & OTHERS 611

.

oes down to dispensing but, when the de^cA^CZated strength, nearly 80 per cent or less ot ti fraud there is Jong reason to *ding room ls being perpetrated in the c i ^ situation ?,r at the dispensing eounter, mixture is demands prompt remedy. cent of the found to contain less than 5 P 0nly to be stated strength of quinine, \ .

pr0duce expected that such a mixture win {rom curative effects on patients suttenng

maJaria- , ,?

n f0r which we were An interesting observation, .

quinine not prepared, is the finding tha a higher sulphate mixtures actually c

-

ted on the Percentage of quinine than that sta mix_ ,

el- Out of 100 quinine and c

^ 16 tures referred to in table 1, insignificant samples were above standard, a

shown figure. Two samples in this gr P ag mUCh as alkaloidal content nearly 1-

pourse not as p the stated strength. This ifl o course bad as a frank deficiency of qui >

ccu'racy in theless, proves gross neglect and maccura y the dispensing service ?

ine tablets The analytical results of 4 qIJnfortunately are summarized in table .TL- r:?in of all details regarding the countries o B

^ the different brands could not or^s 0f 22 rnay however be stated from t represented tablets at our disposal that t y -gur0pean samples of Indian, Javanese

cent) Manufacture. Twenty samples { P

revealed a distinct deficiency of their quinine contents. Of the '

below-strength' tablets, 9 brands (nearly one-third) showed less than 60 per cent of the stated strength of quinine. One

sample contained as low as 6.6 per cent of

quinine, and another brand contained no quinine whatsoever. A redeeming feature of this dismal picture, however, is that quite a number of brands contained nearly 90 per cent of the stated strength of quinine. A slight diminution of the strength of quinine of this type, though not desirable on ethical grounds, is not of any serious significance from the therapeutic view- point. To determine whether the quinine sulphate,

quinine bihydrochloride, and cinchona febrifuge powders, available in the market or supplied to hospitals or dispensaries for preparing stock solutions for daily prescription service, are of standard strength and proper quality, 28 samples were subjected to analysis, both for the content of active principles and for the presence of any adulterants in them. In table III, the origin, the sources from which the samples were

obtained, and the analytical findings of 13

specimens found to be below standard are

presented. Though the data in this group are

meagre, there is sufficient evidence to indicate that at least some quinine salts and preparations sold in the market are below standard. Most of these samples contained as adulterants, in-

organic salts and other cinchona alkaloids. Five

Table I

Quantity of alkaloids in 100 samples

of quinine and cinchona

mixtures

?Alkaloid Percentofdaim

dumber nf UGr ?f samples

Below standard (64)

Nil 0-30

11

30-60

12

60-80

16

80-95

23

Approximately correct (20)

95-105

20

Above standard (16)

105-120 120-140 150-160 180-190

Table II

rp Quinine tablets,

their country of origin

and analytical results

of samples assayed?40 (Indian 10, foreign

12, unknown 18), up to the

standard

20 (50 per cent); below standard?20

(50 per cent).

C?Unt .

Quantity of alkaloid

in per cent of the claim

y ?t origin of below standard samples

in below standard samples

Foreign i Unknown

25 Per cent

6 9

30 per cent I 45 per cent

Nil

1

5 per cent

0-40

3

15 per cent

40-60

5

25 per cent

80-96

11

55 per cent

612 THE INDIAN MEDICAL GAZETTE [Oct., 1939

Table III

Quinine salts and cinchona febrifuge, their country of origin and analytical results Total number of samples assayed?28 (Indian 16, foreign 10, and unknown 2) ; up to tta

standard claimed?15 (53.57 per cent); below standard?13 (46.43 per cent).

Name

Quinine sulphate

Quinine bihydrochloride ..

Cinchona febrifuge

Quinetum

' Ionized quinine'

Total below strength

Total

13

Indian

10

Foreign Result

Inorganic salts and other cinchona alkaloids present.

Anhydrous quinine 79.69 per cent.

Crystallizable alkaloids { Quinine and cinchonidine 47 per cent.

Quinine trace, Sb, A1 and Mg salts present.

samples of cinchona febrifuge (including '

quinetum ') gave from 45 to 65 per cent of

crystallizable alkaloids. As no definite standards have been fixed for cinchona febrifuge, it is difficult to make any comment on the wide variations that are often noticed from sample to sample. However, as the B. P. 1932 has fixed a definite standard for '

totaquina' (70 per cent crystallizable alkaloids), it seems

desirable that all samples of cinchona febrifuge should contain at least 70 per cent of total alkaloids to ensure uniform therapeutic results. Judging from this standard, the cinchona febri- fuge samples tested in this laboratory are defi- nitely below par in quality. A sample of foreign origin, contained as low as 3.30 per cent of

crystallizable alkaloids, which is the lowest

figure on our record. Such a sample is obviously useless and it is surprising how such worthless preparations gain entry into India. A proprietary preparation called ' ionized

quinine' was tested and it was found to contain only a trace of quinine along with certain in-

organic metals and salts. It is not known whether a combination of this type can be of

any therapeutic utility but certainly the name leads the public to believe that the preparation contains at least a certain amount of quinine. The negligible trace of quinine found in it

cannot be expected to do any good in malarial fevers for which the drug is meant to be used. Such preparations are likely to create a false sense of security in the minds of the consumers, and in the interests of the public their sale should be prohibited.

Comment

Medical officers attached to Government or

public hospitals in the mofussil areas have

repeatedly complained that quinine mixtures and tablets have failed to, bring under control cases of malaria under their care. Cases of malaria which are

'

quinine resistant' are also

c

reported from time to time. Clinical reports o

this type have often led to a lack of faith in t

efficacy of quinine as an anti-malarial remedy- In view of the findings presented above, it see111

likely that many fallacies in the field of cluir\1[|e treatment of malaria may be explained by fact that quinine administration in proper dosag was not possible in a large percentage of case^ because of the distribution in the hospitals an

dispensaries in this country of under-streng quinine mixtures, and of the sale in the market of quinine tablets and quinine salts inferior quality. Q

It must be remembered that there are y

variables in clinical therapeutics?the pa^e.,g and the drug. When a particular remedy to bring about an expected cure or alleviatei of symptoms, medical men are prone to look the cause in the patient and try to explain atypical findings, on the basis of the

'

suscej^ tibility ',

' tolerance ' or '

idiosyncrasy G^G'\\l?> the individual. The blame is seldom cast on

drug, as it is naturally believed to be of s^aI!jy ardized quality. This view-point aPPar<jf\])e needs revision. Quinine still remains one of ^ best curative agents in malaria and cases

^ chronic malaria which have been described '

'quinine resistant' must be very rare, if ^

exist at all. ^

Quinine is acknowledged to be one of the ni

important of all drugs for the malaria-stric masses of India. The sale of poor qua

.pg quinine preparations in India or any tamperl.

?

with the quality or strength of quinine Prescr^J tions that may take place in the hospitals & dispensaries, therefore, constitutes one 01

most cruel forms of injury to the public. #

The question that naturally arises in this c

^ nection is?? Is there any remedy for suCi|,at state of affairs ? ' Sir John Megaw thought ^ one of the reasons for the finding of stock

s

tions of quinine under stated strength in saries might be the fraudulent misappropria

?CTv 1939] QUALITY OF QUININE PREPARATIONS : BOSE & OTHERS 613

?* quinine by those responsible ^?.r yn_

Pounding and dispensing of ml* +h' Dart

accurate dispensing and carelessness j.

compounders appear also to b P

er

fetors, as in a few specimens quant^ f ̂

than the stated strength were also jp ;n

Present. A suggestion that has bee

the past is that medical men m charge

of h

Pitals and dispensaries should mstitu e P

p

checking of the quality of the stock fixtures

of

quinine without any previous notice to the

ms

P^sary staff. Megaw, Ghosh and ... J

(1928) described a simple, roughly q

Method of determining the amount

of qumm

quinine mixtures which does not reqmreela

borate laboratory equipment and which

can be

carried out in most of the smaller dispensaries

and hospitals. 1 *?

We are not aware of many hospitals and

ois-

Pensaries where such checking is carried out

regularly and zealously. The truth is that

Judical men in charge of hospitals an

Patients' departments can seldom spare

e

to attend to analytical work and to

the

checking 0f dispensary stock and ml^rev

Prepared therein, in addition to then y

r?utine duties. Even if some medical officers

are enthusiastic enough, they cannot be of

mucn

vice in appraising the quality of Pharmaceu-

cals and galenicals in general, as expert chem

cal and pharmacological knowledge are neces-

sary to carry out drug analysis and assay.

The only way by which this state of

a

can be remedied is to institute some form

o

^ te control by which regular periodic clbee

-

lng and standardization of drugs, both from

hospitals and dispensaries and from the marke,,

ay be carried on in special provincial or c

/al government laboratories, specifically set up

r the purpose and manned by expert ana y

nf i^111 be competent to undertake

the testme

| all kinds of drugs in common use

m clmica

^actice. It seems also imperative that th.

L?+ on pharmacy in India be place

I.

fetter footing so that the ' compounders

who

compound, dispense, or otherwise distribute diug*

jre given such training and status

as to enable

wr?1?! discharge in a more able and .....

Worthy manner the duties and responsibilities

^tached to their calling. Medicine and pha

?fcy are intimately related to each other

an

cannot make any headway without thepother

Progressing also. The profession of pharmacy

n Very poorly developed in

this country

?* to nearly all other civilized countries

is i Wi?r^- Unless this aspect of the pr

L 11 w.ith> all sorts of trickery and

fraud am

^ ccuracies in compounding

and disp

ervice will continue. Definite measures a

urgently called for.

Summary . .

,ne hundred samples of so-called

sam Te '

(deluding cinchona mix ,ur +'_ p;ffht pies of quinine tablets,

and twen y ?

specimens of quinine salts ana cincnona ieun-

fuge powders, obtained from the various provin- cial hospitals and dispensaries through the courtesy of the surgeons-general, inspectors- general and the directors of public health were analysed for their purity and quinine (or total alkaloids) content, according to the methods ana standards laid down in the B. P. 1932, the B. P. C. 1934, and other recognized books of reference.

Eighty '

quinine mixtures ' were found not to

conform to the standards claimed for them.

Sixty-four samples (64 per cent) showed a defi-

ciency of quinine. Curiously enough, as many as sixteen mixtures were found to contain a

higher percentage of quinine than expected. Forty samples of quinine tablets, representing

several different brands of Indian, Javanese and European make, were tested and in this group also, 50 per cent samples showed a deficiency of quinine content. Out of twenty-eight samples of quinine sul-

phate, cinchona febrifuge powders and other miscellaneous solid preparations of this cate- gory, thirteen specimens were found to be below standard. Quinine sulphate powders gave tests for the presence of inorganic salts and other cinchona alkaloids indicating the presence of adulterants in them. Cinchona febrifuge speci- mens were found to contain a considerably lower percentage of the crystallizable alkaloids than that laid down for ' totaquina

' in the B. P. 1932. This survey clearly reveals the unsatisfactory

state of affairs that exists in this country regard- ing the importation, sale, and distribution of an essential remedy for malaria, one which is of

paramount importance to the malaria-stricken I masses of India. It is pointed out that effective I control from this kind of fraud in the drug trade I and dispensing service can only be exercised by

the creation of a state organization for the analysis and standardization of drugs, and also by the improvement of the profession of phar- macy which is at present in a very backward state in India. In view of the gravity of the problem, it seems desirable to institute definite measures to safeguard public health as early as possible.

Acknowledgment The completion of such an extensive survey

is naturally not possible without the co-opera- tion and team work of a number of workers. It is our pleasant duty to acknowledge the help rendered in this work by Mr. R. C. Guha, m.sc., Mr. K. B. Sehra, m.sc., and Mr. B. K. Ghosh, m.sc., our assistant chemists.

References

British Pharmaceutical Codex (1934). Pharmaceutical Press, London.

British Pharmacopoeia (1932). General Medical Council, London. Chopra, R. N., et al. (1931). Re-p. Drugs Enquiry

Committee, 1930-31. Govt, of India Central Publica- tion Branch, Calcutta.

Megaw, J. W. D., Ghosh, S., and Chatterjee, N. R. (1928). Indian Med. Gaz., Vol. LXIII, p. 244.