DEASE AND BRADY ON MICROSCOPICAL VIIP.-On ikIicroscopicu2Research in relation to Pharmacy. By HENRY F.L.S. DEANE,F.L.S. and HENRYB. BRADY [Read at the Bath Meeting of the British Pharmaceutical Conference Sept. 1864.1 WE have chosen for the particular subject of the present commu- nication the various preparations of opium. Whether regarded in respect to their importance in the practice of medicine their variability in strength and character or the peculiar conditions in which the active matter exists in the crude drug no better subject could be found for the purpose in view. Opium as is well known is an extremely composite substance being a pasty mass formed of resinous gummy extractive and albuminous matters containing a larger or srrialler percentage of certain active principles diffused through it.These principles are morphine narcotine (with its two homologuesj codeine narceine mecoiiine thellaine and papaverine either existing free or in com- bination with meconic sulphuric or other acids the sum of the crystalline constituents exclusive of inorganic salts contained in good samples of the drug being from twenty to thirty per cent. of its entire weight. Any preparation exactly to represent opium must contain the whole of' these principles as indeed the tincture may be said fairly to do. It has however been shown that some of the principles are inert and others even deleterious in their action and we have coiisequently had a class of preparations introduced wliich are understood to be of superior efficacy not from their containing any active matter wliich the tincture does not contain but because they aye free from wrtain substances which are retained by it.Narceine meconine and mecoriic acid are believed to be inert whilst narcotine possesses properties widely different from those for which opium is usually employed. Of the bulkier constituents the resiii appears to be worse than useless whereas the bitter extractive though opinions differ with rcgard to its precise pro-perties seems at any rate to increase the narcotic power of the inore active constituents. A typical preparation of ol'ium should therefore at least contain the whole of the morphine and codeine with meconic or sorric other acid to keep them in solution arid the bitter extractive.Codeine itself and tlie salts of both codeine RESEAKCH IN RELATION TO PHARMACY. and morphine are readily soluble in either water or alcohol; the remaining principles are fully dissolved by alcohol but scarcely soluble in water ; hence in the preparations alluded to water rather than alcohol is used as the solvent. The process we adopt in examining the constituents of a fluid preparation of this sort under the microscope is a very simple one. Having as a preliminary step taken the specific gravity and ascertained the percentage of carefully dried extract contained in it we evaporate a small quantity usually from four to six drachms on a sand-bath in a watch-glass to about the consistence of treacle. It is then poured upon a slip of glass and covered with a piece of thin glass and after standing a few days it is sealed in with gold-size.Crystallization sometimes commences before the preparation is removed from the watch-glass sometimes immediately after transferring to the glass slip but in many cases not for several days. The time taken is dependent on one of two influences viz. the quality of the opium and the exact degree of in-spissation. In determining the value of a preparation from the appearance of this extractive under the microscope we do not rely entirely upon the amount of crystallization; it is requisite to go one step further to obtain the full value of our labour and by investigating the form and physical characters of morphine and its compouncis of codeine narcotine meconic acid &c.place ourselves in position to see the significance of the appearance the slide exhibits and to identify any crystalline principles which may be present. Never-theless even in the absence of very accurate kriowledge any one who will make a few experiments for the sake of practice will scon be able by observing the presence or absence the abundance or scarcity of certain forms of crystals easily seen in typical speci- mens to pronounce with little hesitation on the quality or genuine-ness of samples of any of the ordinary preparations of opium. Before proceeding to speak of the opiates which have come under our examination it may seem necessary to say a few words on the forms assumed by the various opium principles and the physical characters their crystals present.This together mitt1 certain drawings we have made carefully from specimens will afford a key to our further remarks. In the first place :-iMorphiiie.-The pure alkaloid crystallizes in right-rhombic prisms n2 DEANE AND BRADY ON MICROSCOPICAL often running into needles. The single crystals have but little effect upon the polarized ray but where the solution has been concentrated (as from alcohol) and the acicular crystals are much overlaid they present a good deal of colour. (Plate I fig. 1.) It is exceedingly difficnlt to say in what condition morphine exists in opium; we are well aware that it has been set down its meconate with a smaller perccntage of sulphate but we have reason to suspect that sulphate is present to a larger extent than is generally supposed.The messing and manipulation which all kinds of opium appear to undergo before they reach this country renders the belief which is suggested by other circumstances that a portion of the meconic acid is decomposed extremely probable. It is scarcely likely that a substance which even boiling water de- composes with evolution of carbonic acid should remain unchanged through the various treatments to which the drug is subjected. Meconate of LWorplhe is set down in chemical works as being uncrystztllizable a statement to be accepted with reservation ;for by careful manipulation peculiar conical crystals may be obtained either from the solution of the commercial salt in dilute alcohol (Plate I fig.3 b.a.) or by the evaporation of mixed solutions of morphine arid meconic acid (Plate I fig. 3 b.6.). These crystals do not resemble any that are found on evaporating opium solutions ; but as we have said the subject requires more investigation than we have as yet been able to give to it. SuZphate of Morphine takes the form of small flat-ended prisms with a strong tendency to collect in radiating tufts; only the larger flat crystals polarized (Plate I fig. 3a). Codeine crystallizes in octahedra running into four-sided prisms. In the octahedral condition it is not easily mistaken for any other of the oplurn-alkaloids but the prisms strongly resemble those of narcotine. (Plate I fig. 4 a). They may be distinguished by their not presenting the fluted or striated surface which crystals of narcotine have and by their much less striking effect on the ray of polarized light.Narcotine occurs in the form of prisms with oblique one-or two-faced ends. As above stated tlie surface of the crystals is fluted or striated and on pressure they break up into tolerably regn!ar smaller crystals (Plate I fig. 2). Owing to a sort of composite structure they have very marked effect on the polarized rap more striking indeed than any other of the opium principles. Were it llot for this propcrty they would be distinguished with great diffi- RESEARCH IN RELATION TO PHARXACY. culty from many other crystalline substances which they resemble in form. There is a tendency as in other cases to cluster together in more or less radiating tufts but the individual crystals still keep their shape and do not degenerate into mere radiating plumose needles like those of narceine.Narceine.-As narceine exists in opium in about the same per-centage on the average as morphine and narcotine it is of greater consequence in these investigations than it is in a medical point of view being probably an inert substance. It is readily soluble in alcohol and slightly so in water aid therefore must exist to con- siderable extent in most of our preparations. The absolute form of the individual crystals it is impossible to determine but the masses of delicate somewhat opaque silky needles either radia- ting from a centre or taking au irregular feathery shape are very characteristic and the absence of any effect on a ray of polarized light is a negative property of importance.(Plate I fig. 6 a). Meconine occurs in six-sided prisms with dihedral summits atid has little if any polarizing power. (Plate I fig. 5 a). Tltebaine is readily soluble in alcohol slightly so in water. From solutions in weak alcohol it crystallizes in beautiful rectan- gular plates often associated in tufts more or less radiating from a centre. (Plate I fig. 4 b). It is a most beautiful polarizing object. Papaverine is present to so trifling an extent that it scarcely requires notice. The little which is dissolved by boiling water crystallizes out again on cooling in minute needles often aggregated ill rounded balls so closely packed as to be quite opaque.The large crystals obtained from the alcoholic solution possess slight polarizing properties (Plate I fig. 6 6). 17leconic Acid-Although the meconate of morphine in opium is an acid salt it seems probable that part of the mcconic acid is also there in a free state j at any rate we frequently find it in preparations. As it is soluble in both alcohol and water prepam- tions are pretty sure to contain whatever quantity does exist in the crude drug unless it has been removed by chemical means The form of the crystals is primarily a square prism but we have only seen this in minute examples and it is very difficult to trace the relationship to this type in the flat pointed lozenges some-what resembling the attenuated forms of' uric acid which gene..rally occur. Even these frequently run into still more stfange varietal shapes whose oiily resemblance to the lozenge-form exists ’DEANE AND BRADY ON MICROSGOPICA& in their broad centres and two pointed ends (Plate I fig.5 6). They all have some effect on the polarized ray. Boiling water decomposes meconic acid; carbonic acid is given off and comenic acid a substance we have not yet studied is formed. We may now proceed to the practical application of the facts enumerated and detail the results of the examination of the many prepsrations which have come under our notice. of Turkey Opium we have investigated-firstly the tincture prepai-ed by ourselves from different samples of opium as well as specimens procured from certain well-known operative chemists ; secondly the extract ; thirdly the wine; fourthly the more or less aqueous solutions sold as Liquor Opii Sed:itivus Battley’s one or two samples prepared by ourselves and specimens procured from four well-known firms ;and fifthly certain proprietary opiates viz.“Black Drop,” ‘‘ Jeremie’s Sedative,” ‘(Nepenthe,” and that sold as “ Solution of Bimeconate of Morphia.” We have drawn careful figures of the appearances presented by the whole of these which will do more than any description towards giving a correct understanding of the facts elicited; at the same time it may be necessary to draw attention to some matters of importance in connection with them. Tincture yields on evaporation crystals of almost the whole of the opium principles and we find that as the spirit volatilizes the resiii is also precipitated in an insoluble form.Our own prepam- tion from different samples of good opium is tolerably constant (Plate 11 fig 1a and b) and agrees in appearance with a speci- men procured from a manufacturing house of some standing (Plate 11 fig. 3) ; but neither are quite sorich in crystalline prin- ciples as a sample furnished to us by our friend Mr. Morson (Plate 11 fig. 2) which Beems to have been prepared from pecu-liarly fine opium. Extracl shows a much smaller proportion of narcotine crystals with abundance of morphine salts and tufts of narceine (Plate 11 fig. 4). Turkey opium is not rich in codeine and we suppose that in extract prepared from it this principle is retained diffiised through the‘ bitter matter.A specimen of conzmercial extract of opium which we have seen recently imported from the East is a very ditl’erent substance showing fewer morphine crystals but a large proportion of codeine (Flate 11 fig. 5). Wine.-The mucilaginous matter of wine very much retards if it does not entirely prevent the formation of crystals upon eva- RESEARCH IN RELATION TO PHARMACY. poration and consequently we can say but little respecting the appearance presented by the extract obtained from vinous solu- tions. Liquor Opii Sedativus.-The styiking appearance resulting from the evaporation of Battley’s Sedative (Plate II1,fig. 1)first drew our attention to the mode of investigation now described.We have examined it frequently and have always met with the same characters. The slides present an almost opaque mass of crystals of morphine-salts and codeine with a very small proportion of narcotine (and meconic acid?) and so far as we have observeci complete absence of resinous matter and narceine. Any one who has studied the microscopic characters of this preparation will readily understand how it has kept its place with the profession. We have necessarily thought much as to its probable mode of preparation and cannot see any reason to doubt the statement made by Dr. Pereira on the authority of the late Mr. Battley himself that spirit and water were the only solvents used in its preparation from Turkey opium.Dr. Christison discredits the statement on the ground of the comparative absence of meconic acid; but as we have before said boiling water is sufficient to decompose that acid and therefore the argument is not a valid one. Though we have experimented much with a view to prepar- ing a similar liquor we have not yet arrived at an i.dentica1 result. PlateIII fig. 2 a and b shows two preparations with similar per- haps nearly equal sedative properties to the original fluid; but it will be seen they both ciiffer considerably in the crystalline matters they contain. The preparation which gives results most nearly like Battley’s of any which we have had opportunity of testing is that made by Mr. Morson of London (Plate 111 fig. 3). Of three other makes which we have examined one (Plate 111 fig.5) is largely charged with resinous matter and the proportion of crystalline constituents is so minute that we are satisfied its activity must be very small; another (Plate 111 fig. 4) gives a few morphine crystals a good deal of narcotine and more nar- ceine; a third (Plate 111 fig. S) is chiefly remarkable for its lack of everything crystalline. There are certain preparations to which we must next allude which give little or no evidence as to the active matters they hold in solution by crystallizatioii on evaporation. As examples we may instance Vinum Opii amongst officinal and Braithwaite’s black drop Nepenthe and a fluid sold as “Solution of Bimeconate 4!0 DEANE AND BRADY ON MICROSCOPICAL of Morphia,” amongst proprietary formulze.That there should be exceptional cases in which the reaction with a certain peculiar set of tests is doubtful is onlp what might have been expected and it can scarcely be regarded as a weak point in their application. Scarcely any chemical test we u~e but is open to some contingency of the same sort but as long as we know the conditions of uncer-tainty it is no drawback to its employment ;it only becomes neces- sary that these conditions should be investigated atid comparison becomes easy. We have found that when opium is exhausted the liquor eva- porated to an extract and this extract redissolved in alcohol tl;e tendency to crystallize is very much lessened or entirely destroyed. The cause of this we are not yet able to explain with certainty but may state the fact as one which we have noticed in relation to every sort of opium we have worked upon.It will account for the very sparing indications of crystalline principles from all preparations made bp redissolving in alcohol a once-formed extract. The residue not taken UJ) by alcohol in the experimcnt is readily soluble in water and contains certain crystalline matters which we have not yet examined sufficiently to report upon. Again the siibacid viscid matter left on evaporating wine prevents crystallization coiisequen tly Vinum Opii gives a clear non-crys tal- line extract ; we believe this also to be the reason why one of the proprietary .preparations named yields the same result as it seems to us to be a mere solution of morphine or one of its salts in wine and not to be made direct from opium.The well known “ black drop” gives no crystals upon evaporation but in their place a peculiar deposit consisting of an amorphous almost opaque fzcu- lence. This is probably owing in great measure to viscid matter held in solution which on evaporation becomes insoluble though Some change and is precipitated carrying clown with it the active matter. We kuow too little of the solvent emFloyed to speak very positively but if the cowmonly received theory be true,-that it is made by a fermentation process in which impure malic acid is concerned,-we can readily understand how viscid orgauic m;ttter may be present in sufficient quantity to produce the result alluded to.In addition to the preparations of Turkey opium we have also llad the opportunity of experimenting on small quantities of the Patna Malwa and Persian varieties arid a11 of them prescrit pecu- liarities of interest. An aqueous extract and a tincture have been RESEARCH IN RELATION TO PHARMACY. made from each and from the Patna sort sufficient has remained to make a specimen of liquor. The most striking fact in connection with the whole of them is the existence of large quantities of codeine. In the extract of Yatna opium (Plate IV fig. 1)it is the chief crystalline constituent and though the liquor (Plate 11 fig. 6) shows abundance of the other opium principles it evidently owes its narcotic effect much more to codeine than Turkey opium does.We have the experi- ence of an opium-eater on this point; he states that the quantity required to produce the effect is larger but there is less discomfort in the after effects than with other sorts. Malwa opium (Blate IV fig. 2 and 5) shows more narcinc and narcotine but in the tinc- ture we have in additioir to a mass of minute crystals certain larger prisms which are probably codeine. Persian opium (Plate IV fig. 3 and 6) also evidently contains a large proportiori of narcotine and codeine. We stated at the commencement that this must be looked upon only as a preliminary research there rsmaiuing many pgints on which our information is far from complete. In continuing the inquiry we intend to devote ourselves chiefly to the elucidation of certain particulars.Firstly the condition or form of Combination in which morphine exists in crude opium ; secofiicily,the relation of extract of poppy to opium in respect to crystallirie principles; and thirdly the influence which the extractive matters may have in altering the crystals obtained in opium solutious and the vnria- tions of the normal forms iiiduced hy this cause. The general conclusions we have arrived at in addition to a knowledge of the appearances presented by typical and special preparations of Turkey Patna Malwa and Persian opiums are mainly these :-That tincture most nearly of any of the preparations represents the properties good and bad of the crude drug. That when crude opium is taken up with proof spirit as in tincture the resin separates on evaporation.That the preparations which have held their ground with the pgblic and the medical profession in spite of their cost differ from the tincture in comparative freedom from resin and narcotine and in containing only a diminished quantity of meconic acid. That in the preparation of extract of opium it is important to use a large quantity of distilled water to ensure the separation of narcotine and resin. DEANE AND BRADY ON MICROSCOPICAL That when extract of opium is dissolved in water filtered and evaporated again to an extract a second or tliird time the crystals frequently differ considerably from those seen in the normal or first formed extract. That when extract of opium is taken up with rectified spirit 56" O.P.and evaporated again to an extract crystallization does not take place or only to R very trifling extent. That morphine and its salts and perhaps other opium principles do not crystallize readily from their solution in wine. Finally it remains for us to express our obligation to our friends Mr. Morson of London and Messrs. T. and €1. Smith of London and Edinburgh for the courteous way in which they have assisted us with specimens when working upon those of the allialoids which exist only in minute quantities in opium ; without this assistance we could scarcely have procured them iu a state of reliable purity. RESEARCH IN RELATION TO PHARMACY. EXPLANATION OF PLATES.PLATE 1. Xmwopical Anewance of Opium Princtples. Fig. 1. Morphine. 2. Narcotine. , 8 a. Sulphate of Morphine. b. Meconate of Morphine. ba. Commercial salt crystallized from solution in weak alcohol. bb. Crystallization from mixed solutions of Morphia and Meconic Acid. Fig. 4 a. Codeine. aa.Cryetallized from Alcoholic solution. ab. Crystallized from Aqueous solution. 6. Thebaine. , 5 a. Meconine. b. Xeconic Acid. ,) 6 a. Narceine. b. Papaverine. bu Crystallized from Alcoholic solution. bb. Crystallized from Aqueous solution. PLATE 11. Fig. 1. Tinctura Opii (Turkey Opium) prepared by the Authors aa standard. , 2 3. Specimens of Tincture alluded to in the text. , 4. Extracturn Opii (Turkey). , 6 a. Commercial Extract of Opiim imported.b. The same redissolved filtered and evaporated. , 6. Liquor Opii Sedativus prepared from Patna Opium. PLATE In. Liquor Opii Sedativus (Turkey Opium). Fig. 1. Battley’s. , 2 a,b. Two specimens prepared by the Authors by elightly differed processes from different samples of opium. , 3. Mr.Morson’s alluded to in the text. , 4 5 6. Specimens sent out by three operative chemists of standing in London. PLATE IT. Fig. 1. Extracturn Opii prepared from Prrtna Opium. 2. , I Malwa Opium. $9 2 9) Peraian Opinm. ’* 8) , 4. Tinctura Opii prepared from Patna Opium. 5. Y , Malwa Opium. #S ? 6. 9 , Persian Opium.