Heckel Analysis Research Articles

Critical analysis of algino-carbopol multiparticulate system for the improvement of flowability, compressibility and tableting properties of a poor flow drug

The objective behind this study is to ameliorate the flowability, compressibility and tableting properties of aceclofenac by developing a prolonged release microparticulate system using an algino-carbopol polymeric blend. Prepared microspheres were subjected to various physico-chemical studies along with in vitro drug release studies to optimize the concentration of the polymeric blend required to sustain the drug release for 12h. Optimize formulation was further subjected to different flowability and compressibility studies to observe the impact of microspheres on improvements of flow properties. All the microsphere formulations exhibited good entrapment efficiency and showed prolonged drug release. SEM study revealed that the microspheres were almost spherical in shape with rough outer surface containing small pores. The findings of micromeritic studies suggested that the flowability and compressibility properties of the pure drug were significantly improved by the microsphere formulation. Heckel analysis also suggested that the microspheres exhibited better plasticity and die filling behavior as compared to pure drug. The tablets containing optimized microspheric formulation showed better handling properties than pure drug and no significant difference in drug release when compared with the marketed product. So the present study concluded that encapsulation of aceclofenac into microparticulate system not only enhanced its flowability, compressibility and tableting properties but also simultaneously helped to improve the patient compliance by sustaining the drug release for a prolonged period of time to manage pain and its symptoms.

Flow, packing and compaction properties of novel coprocessed multifunctional directly compressible excipients prepared from tapioca starch and mannitol

Novel multifunctional excipients were prepared by coprocessing tapioca starch with mannitol using two methods viz; co-grinding and co-fusion. The flow, packing and compaction properties of the native and novel excipients were evaluated by using density, Hausner’s ratio, angle of repose, the maximum volume reduction, consolidation index, the rate of consolidation, angle of internal friction, morphological properties, Heckel analysis, tensile strength and dilution potential as evaluation parameters. The study revealed that the method of coprocessing, particle size and particle shape influenced the properties of the resulting novel excipients. Co-grinding was less effective than co-fusion in the preparation of excipients with enhanced properties. The study concluded that coprocessing tapioca starch and mannitol will enhance the flow, packing and compaction properties of the novel excipient and that the co-fusion method of coprocessing would produce novel excipients with enhanced direct compression potential compared to the co-grinding method.

Yield strength of microcrystalline cellulose: Experimental evidence by dielectric spectroscopy

The water-induced ionic charge transport in compacted microcrystalline cellulose (MCC) has been reported to be governed by the densification behaviour. Hence, mechanical properties were expected to correlate with conductivity behaviour of MCC compacts. Both in-die and out-of-die compaction behaviour of MCC powder was investigated using a fully instrumented rotary tablet press. The dielectric measurements were carried out using a Novocontrol Concept 40 broadband dielectric spectrometer and dc conductivity (σdc) was extracted from the low frequency conductivity data at room temperature. As postulated, compaction pressure corresponding to maximum conductivity (σdc max) was observed to correlate with yield strength of MCC, determined using in-die and out-of-die Heckel analysis. Although Heckel transformation is most commonly used in pharmaceutical technology, its general use to characterise the mechanical properties of organic pharmaceutical materials has been criticized. The present study has provided experimental evidence that Heckel equation is practically useful to describe plastic deformation of organic pharmaceutical powders.

A completely solvent-free process for the improvement of erythritol compactibility

We obtained improvement of erythritol compactibility by formulating composite particles composed of erythritol and porous silica using a twin-screw kneader. Erythritol-based tablets formulated with composite particles were directly compacted, and we estimated their hardness and the friability. The compression properties of the erythritol powder bed including composite particles were estimated using a Heckel analysis and force-displacement profiles, and we investigated the physical states of the composite particles by powder X-ray diffractometry, a thermal analysis and a nitrogen gas adsorption study. A direct-compacted erythritol tablet formulated with composite particles, prepared at the melting temperature of erythritol (120 °C), exhibited high hardness and low friability. A pressure transmission study revealed the higher plasticity and lower elasticity of an erythritol powder bed formulated with composite particles prepared at 120 °C. Physical states of the composite particles indicated that erythritol in the composite particles was adsorbed onto porous silica with a subsequent decrease in the erythritol crystallinity as a result of high mechanical force at the melting temperature of erythritol. The improvement of the erythritol compactibility formulated with composite particles through processing with a twin-screw kneader at 120 °C. This was affected by the reduction of the erythritol crystallinity in the composite particles.

Effect of temperature increase during the tableting of pharmaceutical materials

Scale-up of tableting process is particularly difficult due to specific concerns related exclusively to the process itself and that cannot be determined on a smaller scale, which are the effect of compression speed and the build-up of heat due to the length of the compaction operations. In this work, it has been simulated the rise of temperature observed during the tablets manufacturing in a full production scale by means of an appropriate modification of a R&D rotary tablet machine. Four common pharmaceutical excipients, characterized by different chemical nature, consolidation behaviour and temperature sensitiveness have been analysed in terms of compaction mechanism (Heckel and energy analysis) and tabletability, in order to verify any effect of the increase of temperature. The results showed a relevance of the temperature on mechanical tablets properties only on materials characterized by low temperature thermal transitions (melting or glass transition), while, for compounds which do not exhibit thermal events at low temperature, it becomes less important for ductile materials and irrelevant for brittle materials. Heckel analysis highlighted a noticeable increase of ductility only in those materials whose tablets mechanical properties depended on the temperature. On the other hand, energy analysis showed low sensitivity failing to identify any temperature effect on compaction materials properties. This work showed how to simulate the process of temperature rise on a small scale and the influence of temperature on materials compaction properties. The use of a modified tableting machine, able to control the temperature and moisture levels and also capable of monitoring the punch movements, resulted in identifying the effect of temperature both on mechanical and compaction properties on materials. Thus, it represents a valuable tool in order to provide useful information at an early stage during the development of tablets formulations.

Use of First Derivative of Displacement vs. Force Profiles to Determine Deformation Behavior of Compressed Powders

Displacement (D) vs. force (F) profiles obtained during compaction of powders have been reported by several researchers. These profiles are usually used to obtain mechanical energies associated with the compaction of powders. In this work, we obtained displacement-force data associated with the compression of six powders; Avicel PH101, Avicel PH301, pregelatinized corn starch, anhydrous lactose, dicalcium phosphate, and mannitol. The first three powders are known to deform predominantly by plastic behavior while the later ones are known to deform predominantly by brittle fracture. Displacement-force data was utilized to perform in-die Heckel analysis and to calculate the first derivative (dD/dF) of displacement-force plots. First derivative results were then plotted against mean force (F') at each point and against 1/F' at compression forces between 1 and 20 kN. Results of the in-die Heckle analysis are in very good agreement with the known deformation behavior of the compressed materials. First derivative plots show that materials that deform predominantly by plastic behavior have first derivative values (0.0006-0.0016 mm/ N) larger than those of brittle materials (0.0004 mm/N). Moreover, when dD/dF is plotted against 1/F' for each powder, a linear correlation can be obtained (R2=>0.98). The slopes of the dD/dF vs. 1/F' plots for plastically deforming materials are relatively larger than those for materials that deform by brittle behavior. It is concluded that first derivative plots of displacement-force profiles can be used to determine deformation behavior of powders.

Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs

Polymorphism plays a critical role during pharmaceutical development, as it helps in the selection of optimal solid form. In present study, mechanical properties of ranitidine hydrochloride polymorphs were studied using instrumented tablet press, to understand the effect of crystal packing on the compaction behaviour. Out-of-die compressibility plot and Heckel analysis confirmed greater plastic deformation of form II over form I. Detailed crystallographic examination revealed that form I has several weak C–H⋯O interactions across the ‘proposed slip plane’ parallel to (−2 0 2) that prevent slip under compaction pressure. On the other hand, crystal structure of form II was relatively more open and multiple slip were possible under compaction pressure. These crystallographic features offered increased compressibility and deformability to form II. In absence of an active slip plane system, closed crystal structure of form I resists deformation under compaction pressure and hence showed poor compressibility and higher mean yield pressure. However, form I showed greater tabletability at a given compaction pressure, by virtue of its greater bonding strength.

Evaluation of material properties and compression characteristics of Assam Bora rice flours as a directly compressible vehicle in tablet formulation

Aim: The mechanical properties and compaction characteristics of different varieties of Assam Bora rice flours (ABRFs) were evaluated and compared with those of official Starch 1500®.Methods: The material properties and compression characteristics of Assam Bora rice flours were studied by Heckel and Kawakita analysis. The influences of physical and geometrical properties of ABRFs were evaluated with regard to their compression properties. The mechanical properties, such as toughness and Young's modulus of ABRFs were also compared with that of Starch 1500®.Results: The novel ABRFs reflect better physical characteristics such as higher bulk and tap densities, less porosity, better powder packing ability, large surface area, and improved flowability. ABRFs were the least sensitive material to magnesium stearate, and blending time did not affect its compactibility. Their onset of plastic deformation and strain rate sensitivity as compared to that of Starch 1500® demonstrate its potential use as a directly compressible vehicle for tablet.Conclusions: The experimental ABRFs showed superior properties to official Starch 1500® in many cases and could serve as suitable alternatives for particular purposes.

A systematic and mechanistic evaluation of aspartic acid as filler for directly compressed tablets containing trimethoprim and trimethoprim aspartate

The generally accepted paradigm of ‘inert’ and ‘mono functional’ excipient in dosage form has been recently challenged with the development of individual excipients capable of exhibiting multiple functions (e.g. binder-disintegrants, surfactant which affect P-gp function). The proposed study has been designed within the realm of multifunctionality and is the first and novel investigation towards evaluation of aspartic acid as a filler and disintegration enhancing agent for the delivery of biopharmaceutical class IV model drug trimethoprim. The study investigated powder characteristics using angle of repose, laser diffractometry and scanning electron microscopy (SEM). The prepared tablets were characterised using Heckel analysis, disintegration time and tensile strength measurements. Although Heckel analysis revealed that both TMP and TMP aspartate salt have high elasticity, the salt form produced a stronger compact which was attributed to the formation of agglomerates. Aspartic acid was found to have high plasticity, but its incorporation into the formulations was found to have a negative impact on the compaction properties of TMP and its salt. Surface morphology investigations showed that mechanical interlocking plays a vital role in binding TMP crystals together during compaction, while the small particle size of TMP aspartate agglomerates was found to have significant impact on the tensile strength of the tablets. The study concluded that aspartic acid can be employed as filler and disintegrant and that compactability within tablets was independent of the surface charge of the excipients.

Flow and compaction behaviour of ultrafine coated ibuprofen

Good flow and compaction properties are prerequisites for successful compaction process. Apart from initial profile, mechanical properties of pharmaceutical powders can get modified during unit processes like milling. Milled powders can exhibit a wide range of particle size distribution. Further downstream processing steps like compaction can be affected by this differential particle size distribution. This has greatest implications for formulations like high dose drugs wherein the active pharmaceutical ingredient (API) contributes the maximum bulk in the final formulation. The present study assesses the impact of dry coating with ultrafine particles of same material, on the flow and compaction properties of the core material. Ibuprofen was selected as model drug as it has been reported to have poor mechanical properties. Ultrafine ibuprofen (average size 1.75 μm) was generated by Dyno(®) milling and was dry coated onto the core ibuprofen particles (average size 180 μm). Compaction studies were performed using a fully instrumented rotary tablet press. Compaction data was analyzed for compressibility, tabletability, compactibility profiles and Heckel plot. Dry coating of the ibuprofen exhibited greater compressibility and tabletability, at lower compaction pressure. However, at compaction pressure above 220 MPa, compressibility and tabletability of coated as well as uncoated materials were found to be similar. Heckel analysis also supported the above findings, as P(y) value of uncoated ibuprofen was found to be 229.49 MPa and for 2.0% ultrafine coated ibuprofen was found to be 158.53 MPa. Lower P(y) value of ultrafine coated ibuprofen indicated ease of plastic deformation. Superior compressibility and deformation behaviour of ultrafine coated ibuprofen attributed to increased interparticulate bonding area. This strategy can also be explored for improving tabletability of high dose poorly compressible drugs.

A Systematic Study on Processing Problems and <em>In vitro</em> Release of <em>Saraca indica</em> Caesalpiniaceae Bark Powder Tablets

Purpose: To examine the original flowability, compressibility and compactibility of Saraca indica bark powder and its tablet formulations.Methods: Saraca indica bark powder was subjected to various quantitative tests including acid insoluble ash, total ash, foreign organic matter, alcohol soluble extractive and water soluble extractive. Its flowability and compressibility were determined using Kawakita, Heckel and Leuenberger relationships. Tablets were prepared from the powder by direct compression and wet granulation techniques and characterized. Results: Kawakita analysis revealed lower cohesiveness of granules (3.877 ± 0.890) compared to the powder (6.176 ± 1.030), and hence improved flowability. From Heckel analysis, the higher value of intercept (A) for granules (4.38 ± 0.45) implies higher degree of fragmentation than direct compression DC formulation (2.90 ± 0.33) and powders (2.44 ± 0.12). The compression susceptibility parameter obtained from Leuenberger equation for compacts formed by wet granulation technique (0.183 ± 0.045 1/kg/cm2) indicate that maximum crushing strength is reached faster at lower pressures of compression than for Saraca indica bark powder (0.073 ± 0.025 1/kg/cm2) and DC formulation (0.105 ± 0.033 1/kg/cm2). In-vitro dissolution study showed that more than a 90% of tannin was released within 30 and 60 min from tablets prepared by wet granulation and DC, respectively. Brittle fracture index data indicate that tablets prepared from granules showed less fracture, capping and lamination tendencies.Conclusion: It is concluded that the desired flowability, compressibility and compactibility of Saraca indica bark powder can be obtained by direct compression and wet granulation techniques.

Investigation of the physical–mechanical properties of Eudragit® RS PO/RL PO and their mixtures with common pharmaceutical excipients

Ammonio methacrylate copolymers Eudragit® RS PO and Eudragit® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speed-sensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties.

Characterization of strain rate sensitivity in pharmaceutical materials using indentation creep analysis

Understanding how a material's response to stress changes as the stress is applied at different rates is important in predicting performance of pharmaceutical powders during tablet compression. Widely used methods for determining strain rate sensitivity (SRS) are empirically based and can often provide inconsistent or misleading results. Indentation creep data, collected during hardness tests on compacts formed from several common tableting excipients, were used to predict each material's relative sensitivity to changes in strain rate. Linear relationships between Ln(indentation hardness) and Ln(strain rate) were observed for all materials tested. The slope values taken from these relationships were compared to traditional strain rate sensitivity estimates based on in-die Heckel analysis. Overall, the results from the two methods were quite similar, but several advantages were evident in the creep data. The most notable advantage was the ability to characterize strain rate sensitivity derived from plastic behavior with little influence of elastic deformation. For example, two grades of corn starch had very similar creep behavior, but their yield pressures were affected very differently when the compaction rate was increased. This inconsistency was related to the difference in the viscoelastic recovery exhibited by these two materials. This new method promises to allow a better understanding of strain rate effects observed during tablet manufacturing.

A new perspective on the mechanical evaluation of granular material

The mechanical strength of granules is an important parameter to be determined prior to any further downstream formulation processing. It is important to have a good gauge on the granule integrity to forecast any foreseeable powder issues associated with the material processability such as segregation, content uniformity, and material flow-ability. In this study, a systematic methodology has been developed to quantify the integrity of these granules subjected to a low frequency acoustic field to arrive at the Granule Integrity (GI) index. This methodology has been compared to existing well-established bulk characterization techniques reported in the literature such as Heckel analysis, Kawakita analysis, and Young’s modulus for four different processed samples. Heckel analysis is more amenable to examine the material deformability while Kawakita analysis is better suited to understand the mechanics of granular material. Individual granule strength measurements to determine Young’s modulus often show large variations across the bulk sample. The GI index in conjunction with the Kawakita analysis provides us with more mechanistic insight and understanding into the formation of these granules from a processing perspective. This paper shows the benefits of using the GI index as a practical and direct methodology to characterize the GI of bulk samples in an industrial setting.

Functional and tableting properties of acetylated and oxidised finger millet (Eleusine coracana) starch

AbstractThe functional and tableting properties of native (NaFM) and chemically modified (by acetylation, AcFM; and oxidation, OxFM) finger millet starches were investigated. The tablet formation properties of the starches were assessed by Heckel and Kawakita analysis. The swelling power and solubility of the starch increased with increase in temperature with AcFM having the highest swelling power, while OxFM had the highest solubility. X‐ray diffractometry showed that the starches had the characteristic ‘A’ pattern with strong peaks at 3.78, 4.37, 4.87, and 5.17 Å. Chemical modification causes rupture of some starch granules as revealed by the Scanning Electron Micrograph. Chemical modification also leads to improved gelatinisation profile, with reduction in ΔHgel from 9.64 J/g (NaFM) to 3.88 J/g (AcFM) and 8.76 J/g (OxFM). The bulk density and Hausner's ratio increased after chemical modification of the starch. Chemical modification reduced the mean yield pressure, Py (Heckel analysis) but increased the deformability Pk (Kawakita analysis) of the starch compacts. Chemical modification also increased the crushing and tensile strength of the starch compacts, but lowered its disintegration time and friability.

Grewia Gum 1: Some Mechanical and Swelling Properties of Compact and Film

Purpose: To study the mechanical and dynamic swelling properties of grewia gum, evaluate its compression behaviour and determine the effect of drying methods on its properties.Methods: Compacts (500 mg) of both freeze-dried and air-dried grewia gum were separately prepared by compression on a potassium bromide (KBr) press at different pressures and subjected to Heckel analysis. Swelling studies were performed using 200 mg compacts of the gum (freeze-dried or air-dried) compressed on a KBr press. The mechanical properties of the films of the gum prepared by casting 1 % dispersions of the gum were evaluated using Hounsfield tensiometer. The mechanical properties of grewia gum films were compared with films of pullulan and guar gum which were similarly prepared. The effect of temperature on the water uptake of the compacts was studied and the data subjected toSchott’s analysis. Results: Drying conditions had no effect on the yield pressure of the gum compacts as both air-dried and freeze-dried fractions had a yield pressure of 322.6 MPa. The plots based on Schott’s equation for the grewia gum samples showed that both samples (freeze-dried and air-dried) exhibited long swelling times. Grewia gum film had a tensile strength of 19.22±3.61 MPa which was similar to that of pullulan films (p > 0.05). It had an elastic modulus of 2.13±0.12 N/mm2 which was significantly lower (p < 0.05) than those of pullulan and guar gum with elastic moduli of 3.33±0.00 and 2.86±0.00 N/mm2, respectively.Conclusion: The type of drying method used does not have any effect on the degree of plasticity of grewia gum compacts. Grewia gum obtained by either drying method exhibited extended swelling duration. Matrix tablet formulations of the gum will likely swell slowly and promote sustained release of drug.Keywords: Grewia gum compact, Films, Heckel analysis, Swelling behaviour

Investigation of the impact of insoluble diluents on the compression and release properties of matrix based sustained release tablets

In the present study the effect of insoluble diluents such as microcrystalline cellulose (MCC) and dibasic calcium phosphate (DCP) on the compression characteristics and release profile of sustained release tablets containing Hydroxypropylmethylcellulose (HPMC) matrices was investigated. The effect of diluents on the compression characteristics was studied using Heckel and Kawakita equations. The effect of compression forces on the release profile was also investigated. Diclofenac Sodium (DS) was used as a model drug. Tablets were prepared using wet granulation method. It was found that there is a decrease in the drug release as the concentration of these insoluble diluents is increased. From the Heckel and Kawakita analysis it was concluded that the compressed granules of formulations containing microcrystalline cellulose showed higher plastic deformation, densification and granule fragmentation as compared to DCP. Also a relationship was evaluated between the compression force and the release profile i.e. an increase in compression force causes decrease in the release rate of the drug from the formulation irrespective of change in the diluent.

Physico-mechanical and Stability Evaluation of Carbamazepine Cocrystal with Nicotinamide

The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its preformulation properties and stability profile with CBZ. The cocrystal was prepared by solution cooling crystallization, solvent evaporation, and melting and cryomilling methods. They were characterized for solubility, intrinsic dissolution rate, chemical identification by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. Additionally, mechanical properties were evaluated by tensile strength and Heckel analysis of compacts. The cocrystal and CBZ were stored at 40°C/94% RH, 40°C/75% RH, 25°C/60% RH, and 60°C to determine their stability behavior. The cocrystals were fluffy, with a needle-shaped crystal, and were less dense than CBZ. The solubility profiles of the cocrystals were similar to CBZ, but its intrinsic dissolution rate was lower due to the high tensile strength of its compacts. Unlike CBZ, the cocrystals were resistant to hydrate transformation, as revealed by the stability studies. Plastic deformation started at a higher compression pressure in the cocrystals than CBZ, as indicated by the high yield pressure. In conclusion, the preformulation profile of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation.

The effect of moisture on the heckel and energy analysis of hydroxypropylmethylcellulose 2208 (HPMC K4M).

The influence of moisture content on the Heckel analysis, energy analysis and strain-rate sensitivity of hydroxyproplymethylcellulose 2208 (HPMC K4M) has been evaluated. An increase in moisture content from 0 to 14.9% w/w decreased the mean yield pressure, probably due to a plasticizing effect of moisture which reduced the resistance of particles to deformation. For each moisture content (0, 2.2, 3.8, 5.9, 9.6 and 14.9% w/w), the initial relative density and the extrapolated density from the linear portion of the Heckel plot, tended to decrease with increasing compression speed. Minor changes were observed in the initial relative density due to changes in the moisture content. The strain-rate sensitivity increased from 21.6 to 50.7% as the moisture content increased from 0 to 14.9% w/w, indicating that the plasticity of HPMC increased with increase in moisture content, whereas increase in moisture content from 0 to 14.9% w/w decreased the plastic energy. Increase in compression force or speed of compaction increased both the plastic and elastic energies. An increase in moisture content from 0 to 5.9% w/w slightly reduced the elastic energy but above 5.9% moisture content the elastic energy was unaffected by the moisture content.

Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin

The aim of present research was to investigate the physicochemical, mechanical properties, and stability characteristics of cocrystal of carbamazepine (CBZ) using saccharin (SAC) as a coformer. The cocrystals were prepared by solubility method and characterized by pH-solubility profile, intrinsic dissolution by static disk method, and surface morphology by scanning electron microscopy (SEM), crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and mechanical properties by Heckel analysis. Stability of the cocrystals were assessed by storing them at 60 °C for two weeks, 25 °C/60%RH, 40 °C/75%RH and 40 °C/94%RH for one month and compared with the stability of CBZ. The solubility profile of cocrystal was similar to CBZ. The cocrystal and CBZ have shown the same stability profile at all the conditions of studies except at 40 °C/94%RH. Unlike the CBZ, cocrystal was stable against dihydrate transformation. The compacts of cocrystal have a greater tensile strength and more compressibility. The Heckel analysis suggested that plastic deformation started at low compression pressure in the cocrystal than CBZ. In summary, the cocrystal form of carbamazepine provides another avenue for product development which is more stable than the parent drug.